Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
 
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2020, Vol. 11 Issue (5) : 1235-1259     DOI: 10.14336/AD.2019.1026
Review Article |
Rodent Models of Amyloid-Beta Feature of Alzheimer’s Disease: Development and Potential Treatment Implications
Chi Him Poon1, Yingyi Wang1, Man-Lung Fung1, Chengfei Zhang2, Lee Wei Lim1,*
1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
2Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
Download: PDF(1112 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    
Abstract  

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide and causes severe financial and social burdens. Despite much research on the pathogenesis of AD, the neuropathological mechanisms remain obscure and current treatments have proven ineffective. In the past decades, transgenic rodent models have been used to try to unravel this disease, which is crucial for early diagnosis and the assessment of disease-modifying compounds. In this review, we focus on transgenic rodent models used to study amyloid-beta pathology in AD. We also discuss their possible use as promising tools for AD research. There is still no effective treatment for AD and the development of potent therapeutics are urgently needed. Many molecular pathways are susceptible to AD, ranging from neuroinflammation, immune response, and neuroplasticity to neurotrophic factors. Studying these pathways may shed light on AD pathophysiology as well as provide potential targets for the development of more effective treatments. This review discusses the advantages and limitations of these models and their potential therapeutic implications for AD.

Keywords Alzheimer’s disease      amyloid-beta      neuroinflammation      neuroplasticity      neurotrophic factors     
Corresponding Authors: Lim Lee Wei   
About author:

These authors contributed equally to this work.

Just Accepted Date: 31 March 2020   Issue Date: 21 September 2020
Service
E-mail this article
E-mail Alert
RSS
Articles by authors
Poon Chi Him
Wang Yingyi
Fung Man-Lung
Zhang Chengfei
Lim Lee Wei
Cite this article:   
Poon Chi Him,Wang Yingyi,Fung Man-Lung, et al. Rodent Models of Amyloid-Beta Feature of Alzheimer’s Disease: Development and Potential Treatment Implications[J]. Aging and disease, 2020, 11(5): 1235-1259.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2019.1026     OR
Figure 1.  Timeline illustrating the development of transgenic mouse and rat models of AD.
Animal modelModel backgroundTransgeneAmyloid pathologyOther pathologyBehavioral testRef.
Tg2576C57BL/6Human APP695 (Swedish)Aβ plaques at 10-12 months,oligomeric Aβ generationSynaptic loss at 15-18 months.Behavioral impairment in novel object recognition at 12-15 months, Morris water maze at 6 months and Y maze at 10 months.[55, 123, 237]
TgAPP23C57BL/6JHuman APP751 (Swedish)Aβ plaques at 6 monthsIncreased level of phospho-tau at 6 months, phospho-tau deposition surrounding plaques at 12 months, neuronal loss in area of CA1 at 14-18 months.Behavioral impairment in novel object recognition at 3-4 months, Morris water maze at 3 months.[56, 238, 239]
PDAPPSwiss Webster × B6D2F1Human APP (Indiana)Aβ plaques at 6-9 monthsSynaptic loss.Behavioral impairment in novel object recognition at 6 months, Morris water maze at 3 months.[54, 240]
J20C57BL/6 × DBA/2 F2Human APP (Swedish and Indiana)Diffuse amyloid deposits at 5-6 months and larger neuritic plaques at 9 monthsPhospho-neurofilaments.Behavioral impairment in novel object recognition at 4 months, Morris water maze at 6-9 months.[53, 68, 241, 242]
TgCRND8C3H/He × C57BL/6Human APP695 (Swedish and Indiana)Aβ plaques at 3 months,dense core plaques at 5 months, spreading to the cerebellum and brainstem by 8-9 monthsAstrocytic gliosis and microglial activation in regions around plaques.Behavioral impairment in novel object recognition at 3-5 months, Morris water maze at 3 months.[67, 69, 243]
AppNL-FC57BL/6Human APP (Swedish and Iberian)Aβ plaque at 6 monthsSynaptic loss, microgliosis and astrocytosisBehavioral impairment in Y-maze at 18 months, no impairment in Morris water maze at 18 months[76]
5XFADTg6799×Tg7031 ×Tg7092Human APP (Swedish, Florida, London); Human PS1 (M146L, L286V)Intraneuronal Aβ42 accumulation at 1.5 months, amyloid deposition, gliosis, at 2 monthsSignificant neurodegeneration and neuronal loss.Behavioral impairment in Y-maze at 4-5 months, decreased Interest in social-related behaviors at 3-12 months. Morris water maze at 4 months.[81, 244, 245]
APP23 x PS1-R278IC57BL/6JHuman APP23 (Swedish K651N, M652L); Human PS1 (R278I)Aβ plaque at 6 monthsAstrocytosis.Behavioral impairment in Y-maze at 3-4 months; no significant impairment in Morris water maze[82]
TREM2-BAC x 5XFADTREM2-BAC: FVB/NJ;
5XFAD: C57BL/6X SJL
Human APP (Swedish, Florida, London); Human PS1 (M146L, L286V)less cortical amyloid plaque at 7 months compared to 5XFAD miceEnhanced process ramification and phagocytic marker expression in plaque-associated microglia; improved dystrophic neurites.No cognitive impairment in contextual fear conditioning test.[85]
3xTg-ADC57BL6/129SvJHuman APP (Swedish); Human PS1 (M146V); Human Tau (P301L)Aβ plaque at 6 monthssynaptic dysfunction and increased microglia activation at 6 months; Tau alteration at 12-15 monthsRetention deficits in Morris water maze and contextual fear memory[87-89]
Table 1  Mouse models of amyloid-beta pathology in Alzheimer’s disease.
Animal modelModel backgroundTransgeneAmyloid pathologyOther pathologyBehavioral testRef.
Tg2576C57BL/6Human APP695 (Swedish)Aβ plaques at 10-12 months,oligomeric Aβ generationSynaptic loss at 15-18 months.Behavioral impairment in novel object recognition at 12-15 months, Morris water maze at 6 months and Y maze at 10 months.[55, 123, 237]
TgAPP23C57BL/6JHuman APP751 (Swedish)Aβ plaques at 6 monthsIncreased level of phospho-tau at 6 months, phospho-tau deposition surrounding plaques at 12 months, neuronal loss in area of CA1 at 14-18 months.Behavioral impairment in novel object recognition at 3-4 months, Morris water maze at 3 months.[56, 238, 239]
PDAPPSwiss Webster × B6D2F1Human APP (Indiana)Aβ plaques at 6-9 monthsSynaptic loss.Behavioral impairment in novel object recognition at 6 months, Morris water maze at 3 months.[54, 240]
J20C57BL/6 × DBA/2 F2Human APP (Swedish and Indiana)Diffuse amyloid deposits at 5-6 months and larger neuritic plaques at 9 monthsPhospho-neurofilaments.Behavioral impairment in novel object recognition at 4 months, Morris water maze at 6-9 months.[53, 68, 241, 242]
TgCRND8C3H/He × C57BL/6Human APP695 (Swedish and Indiana)Aβ plaques at 3 months,dense core plaques at 5 months, spreading to the cerebellum and brainstem by 8-9 monthsAstrocytic gliosis and microglial activation in regions around plaques.Behavioral impairment in novel object recognition at 3-5 months, Morris water maze at 3 months.[67, 69, 243]
AppNL-FC57BL/6Human APP (Swedish and Iberian)Aβ plaque at 6 monthsSynaptic loss, microgliosis and astrocytosisBehavioral impairment in Y-maze at 18 months, no impairment in Morris water maze at 18 months[76]
5XFADTg6799×Tg7031 ×Tg7092Human APP (Swedish, Florida, London); Human PS1 (M146L, L286V)Intraneuronal Aβ42 accumulation at 1.5 months, amyloid deposition, gliosis, at 2 monthsSignificant neurodegeneration and neuronal loss.Behavioral impairment in Y-maze at 4-5 months, decreased Interest in social-related behaviors at 3-12 months. Morris water maze at 4 months.[81, 244, 245]
APP23 x PS1-R278IC57BL/6JHuman APP23 (Swedish K651N, M652L); Human PS1 (R278I)Aβ plaque at 6 monthsAstrocytosis.Behavioral impairment in Y-maze at 3-4 months; no significant impairment in Morris water maze[82]
TREM2-BAC x 5XFADTREM2-BAC: FVB/NJ;
5XFAD: C57BL/6X SJL
Human APP (Swedish, Florida, London); Human PS1 (M146L, L286V)less cortical amyloid plaque at 7 months compared to 5XFAD miceEnhanced process ramification and phagocytic marker expression in plaque-associated microglia; improved dystrophic neurites.No cognitive impairment in contextual fear conditioning test.[85]
3xTg-ADC57BL6/129SvJHuman APP (Swedish); Human PS1 (M146V); Human Tau (P301L)Aβ plaque at 6 monthssynaptic dysfunction and increased microglia activation at 6 months; Tau alteration at 12-15 monthsRetention deficits in Morris water maze and contextual fear memory[87-89]
Table 2  Rat models of amyloid-beta pathology in Alzheimer’s disease.
Figure 2.  Human APP695 and APP751 are essential genes involved in the generation of transgenic rodent models of Alzheimer’s disease (AD). Swedish (red), Iberian / Florida (Black) and Indiana / London (Green) are the major mutations introduced into the human APP in rodents to induce rapid amyloid plaque formation. One of the rodent models that encompass numerous mutations is 5XFAD, 3 mutations of which are located on human APP751. Representative photomicrographs showing intense amyloid plaque formation in various brain regions demonstrate severe Aβ pathology in 5XFAD mouse model in the age of 6 months. These images highlight the Aβ pathological progression in brain regions established for memory processes.
[1] Esquerda-Canals G, Montoliu-Gaya L, Guell-Bosch J, Villegas S (2017). Mouse Models of Alzheimer’s Disease. J Alzheimers Dis, 57:1171-1183.
[2] Garre-Olmo J (2018). [Epidemiology of Alzheimer’s disease and other dementias]. Rev Neurol, 66:377-386.
[3] Alzheimer’s Association (2018). 2018 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 14(3):367-429.
[4] Palmer AM (2002). Pharmacotherapy for Alzheimer’s disease: progress and prospects. Trends Pharmacol Sci, 23:426-433.
[5] Gomez-Isla T, Price JL, McKeel DWJr, Morris JC, Growdon JH, Hyman BT (1996). Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci, 16:4491-4500.
[6] Coleman PD, Flood DG (1987). Neuron numbers and dendritic extent in normal aging and Alzheimer’s disease. Neurobiol Aging, 8:521-545.
[7] Fjell AM, Walhovd KB (2010). Structural brain changes in aging: courses, causes and cognitive consequences. Rev Neurosci, 21:187-221.
[8] Ball MJ (1977). Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol, 37:111-118.
[9] Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC (2001). Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol, 58:1395-1402.
[10] Simic G, Kostovic I, Winblad B, Bogdanovic N (1997). Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease. J Comp Neurol, 379:482-494.
[11] ter Laak HJ, Renkawek K, van Workum FP (1994). The olfactory bulb in Alzheimer disease: a morphologic study of neuron loss, tangles, and senile plaques in relation to olfaction. Alzheimer Dis Assoc Disord, 8:38-48.
[12] Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR (1981). Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol, 10:122-126.
[13] Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR (1982). Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science, 215:1237-1239.
[14] Zarow C, Lyness SA, Mortimer JA, Chui HC (2003). Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol, 60:337-341.
[15] Weinshenker D (2008). Functional consequences of locus coeruleus degeneration in Alzheimer’s disease. Curr Alzheimer Res, 5:342-345.
[16] Meltzer CC, Smith G, DeKosky ST, Pollock BG, Mathis CA, Moore RY, et al. (1998). Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology, 18:407-430.
[17] Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, et al. (2003). Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology, 60:1495-1500.
[18] Li B, Yamamori H, Tatebayashi Y, Shafit-Zagardo B, Tanimukai H, Chen S, et al. (2008). Failure of neuronal maturation in Alzheimer disease dentate gyrus. J Neuropathol Exp Neurol, 67:78-84.
[19] Ziabreva I, Perry E, Perry R, Minger SL, Ekonomou A, Przyborski S, et al. (2006). Altered neurogenesis in Alzheimer’s disease. J Psychosom Res, 61:311-316.
[20] Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, et al. (2004). Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A, 101:343-347.
[21] Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995). An English translation of Alzheimer’s 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat, 8:429-431.
[22] Kidd M (1963). Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature, 197:192-193.
[23] Wisniewski HM, Narang HK, Terry RD (1976). Neurofibrillary tangles of paired helical filaments. J Neurol Sci, 27:173-181.
[24] Lee VM, Balin BJ, Otvos LJr, Trojanowski JQ (1991). A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science, 251:675-678.
[25] Mesulam MM, Asuncion Moran M (1987). Cholinesterases within neurofibrillary tangles related to age and Alzheimer’s disease. Ann Neurol, 22:223-228.
[26] Perry G, Friedman R, Shaw G, Chau V (1987). Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci U S A, 84:3033-3036.
[27] Love S, Saitoh T, Quijada S, Cole GM, Terry RD (1988). Alz-50, ubiquitin and tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J Neuropathol Exp Neurol, 47:393-405.
[28] Hyman BT, Van Hoesen GW, Beyreuther K, Masters CL (1989). A4 amyloid protein immunoreactivity is present in Alzheimer’s disease neurofibrillary tangles. Neurosci Lett, 101:352-355.
[29] Morrison JH, Hof PR (1997). Life and death of neurons in the aging brain. Science, 278:412-419.
[30] Bierer LM, Hof PR, Purohit DP, Carlin L, Schmeidler J, Davis KL, et al. (1995). Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer’s disease. Arch Neurol, 52:81-88.
[31] Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992). Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology, 42:631-639.
[32] Medeiros R, LaFerla FM (2013). Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol, 239:133-138.
[33] Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2010). Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia, 58:831-838.
[34] Perl DP (2010). Neuropathology of Alzheimer’s disease. Mt Sinai J Med, 77:32-42.
[35] Streit WJ, Mrak RE, Griffin WS (2004). Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation, 1:14.
[36] Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al. (1987). The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature, 325:733-736.
[37] Selkoe DJ, Yamazaki T, Citron M, Podlisny MB, Koo EH, Teplow DB, et al. (1996). The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Ann N Y Acad Sci, 777:57-64.
[38] Selkoe DJ (1998). The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol, 8:447-453.
[39] Selkoe DJ (2001). Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev, 81:741-766.
[40] Prelli F, Castano E, Glenner GG, Frangione B (1988). Differences between vascular and plaque core amyloid in Alzheimer’s disease. J Neurochem, 51:648-651.
[41] Hardy JA, Higgins GA (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science, 256:184-185.
[42] Hardy J (2006). Has the amyloid cascade hypothesis for Alzheimer’s disease been proved? Curr Alzheimer Res, 3:71-73.
[43] LaFerla FM, Green KN, Oddo S (2007). Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci, 8:499-509.
[44] Do Carmo S, Cuello AC (2013). Modeling Alzheimer’s disease in transgenic rats. Mol Neurodegener, 8:37.
[45] Dyrks T, Dyrks E, Masters CL, Beyreuther K (1993). Amyloidogenicity of rodent and human beta A4 sequences. FEBS Lett, 324:231-236.
[46] Martino Adami PV, Quijano C, Magnani N, Galeano P, Evelson P, Cassina A, et al. (2017). Synaptosomal bioenergetic defects are associated with cognitive impairment in a transgenic rat model of early Alzheimer’s disease. J Cereb Blood Flow Metab, 37:69-84.
[47] Skaper SD (2012). Alzheimer’s disease and amyloid: culprit or coincidence? Int Rev Neurobiol, 102:277-316.
[48] Guzman EA, Bouter Y, Richard BC, Lannfelt L, Ingelsson M, Paetau A, et al. (2014). Abundance of Abeta(5)-x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer’s disease. Mol Neurodegener, 9:13.
[49] Reinert J, Martens H, Huettenrauch M, Kolbow T, Lannfelt L, Ingelsson M, et al. (2014). Abeta38 in the brains of patients with sporadic and familial Alzheimer’s disease and transgenic mouse models. J Alzheimers Dis, 39:871-881.
[50] Futai E, Osawa S, Cai T, Fujisawa T, Ishiura S, Tomita T (2016). Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate gamma-Secretase Activities. J Biol Chem, 291:435-446.
[51] Buxbaum JD, Christensen JL, Ruefli AA, Greengard P, Loring JF (1993). Expression of APP in brains of transgenic mice containing the entire human APP gene. Biochem Biophys Res Commun, 197:639-645.
[52] Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, Kearns WG, et al. (1993). Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected]. Nat Genet, 5:22-30.
[53] Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, et al. (2000). High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci, 20:4050-4058.
[54] Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, et al. (1995). Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature, 373:523-527.
[55] Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. (1996). Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science, 274:99-102.
[56] Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, et al. (1997). Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A, 94:13287-13292.
[57] Kitazawa M, Medeiros R, Laferla FM (2012). Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. Curr Pharm Des, 18:1131-1147.
[58] Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, et al. (1995). Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron, 15:1203-1218.
[59] Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, et al. (2006). A specific amyloid-beta protein assembly in the brain impairs memory. Nature, 440:352-357.
[60] Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT (1997). APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol, 56:965-973.
[61] Spires-Jones TL, Meyer-Luehmann M, Osetek JD, Jones PB, Stern EA, Bacskai BJ, et al. (2007). Impaired spine stability underlies plaque-related spine loss in an Alzheimer’s disease mouse model. Am J Pathol, 171:1304-1311.
[62] Beckmann N, Schuler A, Mueggler T, Meyer EP, Wiederhold KH, Staufenbiel M, et al. (2003). Age-dependent cerebrovascular abnormalities and blood flow disturbances in APP23 mice modeling Alzheimer’s disease. J Neurosci, 23:8453-8459.
[63] Mueggler T, Sturchler-Pierrat C, Baumann D, Rausch M, Staufenbiel M, Rudin M (2002). Compromised hemodynamic response in amyloid precursor protein transgenic mice. J Neurosci, 22:7218-7224.
[64] Calhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, et al. (1998). Neuron loss in APP transgenic mice. Nature, 395:755-756.
[65] Rockenstein EM, McConlogue L, Tan H, Power M, Masliah E, Mucke L (1995). Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer’s disease. J Biol Chem, 270:28257-28267.
[66] Irizarry MC, Soriano F, McNamara M, Page KJ, Schenk D, Games D, et al. (1997). Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci, 17:7053-7059.
[67] Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, et al. (2001). Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem, 276:21562-21570.
[68] Ameen-Ali KE, Wharton SB, Simpson JE, Heath PR, Sharp P, Berwick J (2017). Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer’s disease. Neuropathol Appl Neurobiol, 43:553-570.
[69] Kobayashi DT, Chen KS (2005). Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer’s disease. Genes Brain Behav, 4:173-196.
[70] Harris JA, Devidze N, Halabisky B, Lo I, Thwin MT, Yu GQ, et al. (2010). Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer’s disease are independent of caspase cleavage of the amyloid precursor protein. J Neurosci, 30:372-381.
[71] Bellucci A, Luccarini I, Scali C, Prosperi C, Giovannini MG, Pepeu G, et al. (2006). Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice. Neurobiol Dis, 23:260-272.
[72] Chen S, Yadav SP, Surewicz WK (2010). Interaction between human prion protein and amyloid-beta (Abeta) oligomers: role OF N-terminal residues. J Biol Chem, 285:26377-26383.
[73] Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, et al. (2010). A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci, 30:4845-4856.
[74] McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, et al. (1999). Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol, 46:860-866.
[75] Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, et al. (2000). Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. Jama, 283:1571-1577.
[76] Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, et al. (2014). Single App knock-in mouse models of Alzheimer’s disease. Nat Neurosci, 17:661-663.
[77] Chui DH, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, et al. (1999). Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med, 5:560-564.
[78] Rutten BP, Van der Kolk NM, Schafer S, van Zandvoort MA, Bayer TA, Steinbusch HW, et al. (2005). Age-related loss of synaptophysin immunoreactive presynaptic boutons within the hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L transgenic mice. Am J Pathol, 167:161-173.
[79] Sadowski M, Pankiewicz J, Scholtzova H, Ji Y, Quartermain D, Jensen CH, et al. (2004). Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. J Neuropathol Exp Neurol, 63:418-428.
[80] Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, et al. (1997). Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron, 19:939-945.
[81] Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. (2006). Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci, 26:10129-10140.
[82] Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, et al. (2011). Potent amyloidogenicity and pathogenicity of Abeta43. Nat Neurosci, 14:1023-1032.
[83] Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, et al. (2002). Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet, 71:656-662.
[84] Guerreiro RJ, Lohmann E, Bras JM, Gibbs JR, Rohrer JD, Gurunlian N, et al. (2013). Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol, 70:78-84.
[85] Lee CYD, Daggett A, Gu X, Jiang LL, Langfelder P, Li X, et al. (2018). Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models. Neuron, 97:1032-1048.e1035.
[86] Song WM, Joshita S, Zhou Y, Ulland TK, Gilfillan S, Colonna M (2018). Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med, 215:745-760.
[87] Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. (2003). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron, 39:409-421.
[88] Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005). Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron, 45:675-688.
[89] Belfiore R, Rodin A, Ferreira E, Velazquez R, Branca C, Caccamo A, et al. (2019). Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice. Aging Cell, 18:e12873.
[90] Pooler AM, Polydoro M, Maury EA, Nicholls SB, Reddy SM, Wegmann S, et al. (2015). Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease. Acta Neuropathol Commun, 3:14.
[91] Pascoal TA, Mathotaarachchi S, Mohades S, Benedet AL, Chung CO, Shin M, et al. (2017). Amyloid-beta and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease. Mol Psychiatry, 22:306-311.
[92] Echeverria V, Ducatenzeiler A, Alhonen L, Janne J, Grant SM, Wandosell F, et al. (2004). Rat transgenic models with a phenotype of intracellular Abeta accumulation in hippocampus and cortex. J Alzheimers Dis, 6:209-219.
[93] Echeverria V, Ducatenzeiler A, Dowd E, Janne J, Grant SM, Szyf M, et al. (2004). Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the beta-amyloid peptide intracellularly in hippocampal and cortical neurons. Neuroscience, 129:583-592.
[94] Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LR, Herrera VL (2004). Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Mol Med, 10:36-44.
[95] Benedikz E, Kloskowska E, Winblad B (2009). The rat as an animal model of Alzheimer’s disease. J Cell Mol Med, 13:1034-1042.
[96] Folkesson R, Malkiewicz K, Kloskowska E, Nilsson T, Popova E, Bogdanovic N, et al. (2007). A transgenic rat expressing human APP with the Swedish Alzheimer’s disease mutation. Biochem Biophys Res Commun, 358:777-782.
[97] Kloskowska E, Pham TM, Nilsson T, Zhu S, Oberg J, Codita A, et al. (2010). Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer’s disease. J Cell Mol Med, 14:1816-1823.
[98] Johnson SA, Rogers J, Finch CE (1989). APP-695 transcript prevalence is selectively reduced during Alzheimer’s disease in cortex and hippocampus but not in cerebellum. Neurobiol Aging, 10:755-760.
[99] Clarke J, Thornell A, Corbett D, Soininen H, Hiltunen M, Jolkkonen J (2007). Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur J Neurosci, 26:1845-1852.
[100] Whitehead S, Cheng G, Hachinski V, Cechetto DF (2005). Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: II. Effects of triflusal. Stroke, 36:1782-1789.
[101] Brody DL, Holtzman DM (2006). Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury. Exp Neurol, 197:330-340.
[102] Popa-Wagner A, Schroder E, Walker LC, Kessler C (1998). beta-Amyloid precursor protein and ss-amyloid peptide immunoreactivity in the rat brain after middle cerebral artery occlusion: effect of age. Stroke, 29:2196-2202.
[103] Nihashi T, Inao S, Kajita Y, Kawai T, Sugimoto T, Niwa M, et al. (2001). Expression and distribution of beta amyloid precursor protein and beta amyloid peptide in reactive astrocytes after transient middle cerebral artery occlusion. Acta Neurochir (Wien), 143:287-295.
[104] Agca C, Fritz JJ, Walker LC, Levey AI, Chan AW, Lah JJ, et al. (2008). Development of transgenic rats producing human beta-amyloid precursor protein as a model for Alzheimer’s disease: transgene and endogenous APP genes are regulated tissue-specifically. BMC Neurosci, 9:28.
[105] Weishaupt N, Liu Q, Shin S, Singh R, Agca Y, Agca C, et al. (2018). APP21 transgenic rats develop age-dependent cognitive impairment and microglia accumulation within white matter tracts. J Neuroinflammation, 15:241.
[106] Flood DG, Lin YG, Lang DM, Trusko SP, Hirsch JD, Savage MJ, et al. (2009). A transgenic rat model of Alzheimer’s disease with extracellular Abeta deposition. Neurobiol Aging, 30:1078-1090.
[107] Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, et al. (2008). A transgenic rat that develops Alzheimer’s disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiol Dis, 31:46-57.
[108] Zahorsky-Reeves J LG, Chu DK, Schimmel A, Ezell PC, Dang M, Couto M (2007). Maintaining longevity in a triple transgenic rat model of Alzheimer’s disease. Am Assoc Lab Anim Sci, 46:124.
[109] Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, et al. (2013). A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci, 33:6245-6256.
[110] Rorabaugh JM, Chalermpalanupap T, Botz-Zapp CA, Fu VM, Lembeck NA, Cohen RM, et al. (2017). Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease. Brain, 140:3023-3038.
[111] Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, et al. (2010). A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis, 20:113-126.
[112] Galeano P, Martino Adami PV, Do Carmo S, Blanco E, Rotondaro C, Capani F, et al. (2014). Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer’s disease. Front Behav Neurosci, 8:321.
[113] Agca C, Klakotskaia D, Schachtman TR, Chan AW, Lah JJ, Agca Y (2016). Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention. BMC Neurosci, 17:46.
[114] Klakotskaia D, Agca C, Richardson RA, Stopa EG, Schachtman TR, Agca Y (2018). Memory deficiency, cerebral amyloid angiopathy, and amyloid-beta plaques in APP+PS1 double transgenic rat model of Alzheimer’s disease. PLoS One, 13:e0195469.
[115] Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, et al. (2004). Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature, 428:493-521.
[116] Jacob HJ, Kwitek AE (2002). Rat genetics: attaching physiology and pharmacology to the genome. Nat Rev Genet, 3:33-42.
[117] Lin JH (1995). Species similarities and differences in pharmacokinetics. Drug Metab Dispos, 23:1008-1021.
[118] McLean JW, Fukazawa C, Taylor JM (1983). Rat apolipoprotein E mRNA. Cloning and sequencing of double-stranded cDNA. J Biol Chem, 258:8993-9000.
[119] Rajavashisth TB, Kaptein JS, Reue KL, Lusis AJ (1985). Evolution of apolipoprotein E: mouse sequence and evidence for an 11-nucleotide ancestral unit. Proc Natl Acad Sci U S A, 82:8085-8089.
[120] Tesson L, Cozzi J, Menoret S, Remy S, Usal C, Fraichard A, et al. (2005). Transgenic modifications of the rat genome. Transgenic Res, 14:531-546.
[121] Whishaw IQ, Metz GA, Kolb B, Pellis SM (2001). Accelerated nervous system development contributes to behavioral efficiency in the laboratory mouse: a behavioral review and theoretical proposal. Dev Psychobiol, 39:151-170.
[122] Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K (2019). Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement (N Y), 5:272-293.
[123] Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, et al. (2002). The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci, 22:1858-1867.
[124] Buccafusco JJ2009. Frontiers in Neuroscience. In Methods of Behavior Analysis in Neuroscience. BuccafuscoJJ, editor. Boca Raton (FL): CRC Press/Taylor & Francis Taylor & Francis Group, LLC.
[125] Sweeney MD, Sagare AP, Zlokovic BV (2018). Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol, 14:133-150.
[126] Hensley K (2010). Neuroinflammation in Alzheimer’s disease: mechanisms, pathologic consequences, and potential for therapeutic manipulation. J Alzheimers Dis, 21:1-14.
[127] in t’ Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, et al. (2001). Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med, 345:1515-1521.
[128] Sofroniew MV (2009). Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci, 32:638-647.
[129] Sofroniew MV, Vinters HV (2010). Astrocytes: biology and pathology. Acta Neuropathol, 119:7-35.
[130] Kummer MP, Hammerschmidt T, Martinez A, Terwel D, Eichele G, Witten A, et al. (2014). Ear2 deletion causes early memory and learning deficits in APP/PS1 mice. J Neurosci, 34:8845-8854.
[131] Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2011). Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer’s disease mouse model: mechanism for deficient glutamatergic transmission? Mol Neurodegener, 6:55.
[132] Yeh CY, Vadhwana B, Verkhratsky A, Rodriguez JJ (2011). Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer’s disease. ASN Neuro, 3:271-279.
[133] Kulijewicz-Nawrot M, Verkhratsky A, Chvatal A, Sykova E, Rodriguez JJ (2012). Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J Anat, 221:252-262.
[134] Beauquis J, Pavia P, Pomilio C, Vinuesa A, Podlutskaya N, Galvan V, et al. (2013). Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer’s disease. Exp Neurol, 239:28-37.
[135] Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, et al. (2012). Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci, 32:16129-16140.
[136] Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, et al. (2008). ApoE promotes the proteolytic degradation of Abeta. Neuron, 58:681-693.
[137] Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JA, Holtzman DM, et al. (2011). Critical role of astroglial apolipoprotein E and liver X receptor-alpha expression for microglial Abeta phagocytosis. J Neurosci, 31:7049-7059.
[138] Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. (2003). Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med, 9:453-457.
[139] Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011). Physiology of microglia. Physiol Rev, 91:461-553.
[140] Ji K, Akgul G, Wollmuth LP, Tsirka SE (2013). Microglia actively regulate the number of functional synapses. PLoS One, 8:e56293.
[141] Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE (2003). A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci, 23:2665-2674.
[142] Paresce DM, Ghosh RN, Maxfield FR (1996). Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor. Neuron, 17:553-565.
[143] Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. (2010). CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol, 11:155-161.
[144] Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, et al. (2005). LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain, 128:1778-1789.
[145] El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, et al. (2003). CD36 mediates the innate host response to beta-amyloid. J Exp Med, 197:1657-1666.
[146] Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, et al. (2013). CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol, 14:812-820.
[147] Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006). Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron, 49:489-502.
[148] El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, et al. (2007). Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med, 13:432-438.
[149] Stewart WF, Kawas C, Corrada M, Metter EJ (1997). Risk of Alzheimer’s disease and duration of NSAID use. Neurology, 48:626-632.
[150] Gasparini L, Ongini E, Wenk G (2004). Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer’s disease: old and new mechanisms of action. J Neurochem, 91:521-536.
[151] Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. (2001). A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature, 414:212-216.
[152] McKee AC, Carreras I, Hossain L, Ryu H, Klein WL, Oddo S, et al. (2008). Ibuprofen reduces Abeta, hyperphosphorylated tau and memory deficits in Alzheimer mice. Brain Res, 1207:225-236.
[153] Lim GP, Yang F, Chu T, Gahtan E, Ubeda O, Beech W, et al. (2001). Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging, 22:983-991.
[154] Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP, Koo EH, et al. (2007). Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci, 8:54.
[155] Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, et al. (2005). Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain, 128:1442-1453.
[156] Carreras I, McKee AC, Choi JK, Aytan N, Kowall NW, Jenkins BG, et al. (2013). R-flurbiprofen improves tau, but not Ass pathology in a triple transgenic model of Alzheimer’s disease. Brain Res, 1541:115-127.
[157] Jaturapatporn D, Isaac MG, McCleery J, Tabet N (2012). Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev:Cd006378.
[158] Heneka MT, Fink A, Doblhammer G (2015). Effect of pioglitazone medication on the incidence of dementia. Ann Neurol, 78:284-294.
[159] Hu WT, Holtzman DM, Fagan AM, Shaw LM, Perrin R, Arnold SE, et al. (2012). Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology, 79:897-905.
[160] Jahrling JB, Hernandez CM, Denner L, Dineley KT (2014). PPARgamma recruitment to active ERK during memory consolidation is required for Alzheimer’s disease-related cognitive enhancement. J Neurosci, 34:4054-4063.
[161] Denner LA, Rodriguez-Rivera J, Haidacher SJ, Jahrling JB, Carmical JR, Hernandez CM, et al. (2012). Cognitive enhancement with rosiglitazone links the hippocampal PPARgamma and ERK MAPK signaling pathways. J Neurosci, 32:16725-16735a.
[162] McCoy MK, Tansey MG (2008). TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation, 5:45.
[163] He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, et al. (2007). Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol, 178:829-841.
[164] Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW, et al. (2011). Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res, 1368:239-247.
[165] Matsuda H, Coughlin MD, Bienenstock J, Denburg JA (1988). Nerve growth factor promotes human hemopoietic colony growth and differentiation. Proc Natl Acad Sci U S A, 85:6508-6512.
[166] Meng X, Lindahl M, Hyvonen ME, Parvinen M, de Rooij DG, Hess MW, et al. (2000). Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science, 287:1489-1493.
[167] Lavasani M, Lu A, Peng H, Cummins J, Huard J (2006). Nerve growth factor improves the muscle regeneration capacity of muscle stem cells in dystrophic muscle. Hum Gene Ther, 17:180-192.
[168] The BDNF study group (1999). A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF Study Group (Phase III). Neurology, 52:1427-1433.
[169] Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, et al. (2008). Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology, 71:1770-1775.
[170] Aebischer P, Schluep M, Deglon N, Joseph JM, Hirt L, Heyd B, et al. (1996). Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat Med, 2:696-699.
[171] Beck M, Flachenecker P, Magnus T, Giess R, Reiners K, Toyka KV, et al. (2005). Autonomic dysfunction in ALS: a preliminary study on the effects of intrathecal BDNF. Amyotroph Lateral Scler Other Motor Neuron Disord, 6:100-103.
[172] Herzog CD, Bishop KM, Brown L, Wilson A, Kordower JH, Bartus RT (2011). Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. Drug Deliv Transl Res, 1:361-382.
[173] Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, et al. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med, 11:551-555.
[174] Pertusa M, Garcia-Matas S, Mammeri H, Adell A, Rodrigo T, Mallet J, et al. (2008). Expression of GDNF transgene in astrocytes improves cognitive deficits in aged rats. Neurobiol Aging, 29:1366-1379.
[175] Revilla S, Ursulet S, Alvarez-Lopez MJ, Castro-Freire M, Perpina U, Garcia-Mesa Y, et al. (2014). Lenti-GDNF gene therapy protects against Alzheimer’s disease-like neuropathology in 3xTg-AD mice and MC65 cells. CNS Neurosci Ther, 20:961-972.
[176] Voineskos AN, Lerch JP, Felsky D, Shaikh S, Rajji TK, Miranda D, et al. (2011). The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. Arch Gen Psychiatry, 68:198-206.
[177] Sandhya VK, Raju R, Verma R, Advani J, Sharma R, Radhakrishnan A, et al. (2013). A network map of BDNF/TRKB and BDNF/p75NTR signaling system. J Cell Commun Signal, 7:301-307.
[178] Leyhe T, Stransky E, Eschweiler GW, Buchkremer G, Laske C (2008). Increase of BDNF serum concentration during donepezil treatment of patients with early Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci, 258:124-128.
[179] Autio H, Matlik K, Rantamaki T, Lindemann L, Hoener MC, Chao M, et al. (2011). Acetylcholinesterase inhibitors rapidly activate Trk neurotrophin receptors in the mouse hippocampus. Neuropharmacology, 61:1291-1296.
[180] Sakr HF, Khalil KI, Hussein AM, Zaki MS, Eid RA, Alkhateeb M (2014). Effect of dehydroepiandrosterone (DHEA) on memory and brain derived neurotrophic factor (BDNF) in a rat model of vascular dementia. J Physiol Pharmacol, 65:41-53.
[181] Bae CY, Cho CY, Cho K, Hoon Oh B, Choi KG, Lee HS, et al. (2000). A double-blind, placebo-controlled, multicenter study of Cerebrolysin for Alzheimer’s disease. J Am Geriatr Soc, 48:1566-1571.
[182] Ruther E, Ritter R, Apecechea M, Freytag S, Gmeinbauer R, Windisch M (2000). Sustained improvements in patients with dementia of Alzheimer’s type (DAT) 6 months after termination of Cerebrolysin therapy. J Neural Transm (Vienna), 107:815-829.
[183] Masliah E, Armasolo F, Veinbergs I, Mallory M, Samuel W (1999). Cerebrolysin ameliorates performance deficits, and neuronal damage in apolipoprotein E-deficient mice. Pharmacol Biochem Behav, 62:239-245.
[184] Horner PJ, Gage FH (2000). Regenerating the damaged central nervous system. Nature, 407:963-970.
[185] Brewer GJ (1999). Regeneration and proliferation of embryonic and adult rat hippocampal neurons in culture. Exp Neurol, 159:237-247.
[186] Seaberg RM, van der Kooy D (2002). Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci, 22:1784-1793.
[187] Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999). Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci, 2:260-265.
[188] Cameron HA, McKay RD (1999). Restoring production of hippocampal neurons in old age. Nat Neurosci, 2:894-897.
[189] Flax JD, Aurora S, Yang C, Simonin C, Wills AM, Billinghurst LL, et al. (1998). Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotechnol, 16:1033-1039.
[190] Zhou W, Raisman G, Zhou C (1998). Transplanted embryonic entorhinal neurons make functional synapses in adult host hippocampus. Brain Res, 788:202-206.
[191] Ono K, Takii T, Onozaki K, Ikawa M, Okabe M, Sawada M (1999). Migration of exogenous immature hematopoietic cells into adult mouse brain parenchyma under GFP-expressing bone marrow chimera. Biochem Biophys Res Commun, 262:610-614.
[192] Sofroniew MV, Howe CL, Mobley WC (2001). Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci, 24:1217-1281.
[193] Knipper M, da Penha Berzaghi M, Blochl A, Breer H, Thoenen H, Lindholm D (1994). Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci, 6:668-671.
[194] Holtzman DM, Kilbridge J, Li Y, Cunningham ETJr, Lenn NJ, Clary DO, et al. (1995). TrkA expression in the CNS: evidence for the existence of several novel NGF-responsive CNS neurons. J Neurosci, 15:1567-1576.
[195] Rattray M (2001). Is there nicotinic modulation of nerve growth factor? Implications for cholinergic therapies in Alzheimer’s disease. Biol Psychiatry, 49:185-193.
[196] Mobley WC, Rutkowski JL, Tennekoon GI, Buchanan K, Johnston MV (1985). Choline acetyltransferase activity in striatum of neonatal rats increased by nerve growth factor. Science, 229:284-287.
[197] Higgins GA, Koh S, Chen KS, Gage FH (1989). NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat. Neuron, 3:247-256.
[198] Heisenberg CP, Cooper JD, Berke J, Sofroniew MV (1994). NMDA potentiates NGF-induced sprouting of septal cholinergic fibres. Neuroreport, 5:413-416.
[199] Jette N, Cole MS, Fahnestock M (1994). NGF mRNA is not decreased in frontal cortex from Alzheimer’s disease patients. Brain Res Mol Brain Res, 25:242-250.
[200] Scott SA, Mufson EJ, Weingartner JA, Skau KA, Crutcher KA (1995). Nerve growth factor in Alzheimer’s disease: increased levels throughout the brain coupled with declines in nucleus basalis. J Neurosci, 15:6213-6221.
[201] Hock C, Heese K, Muller-Spahn F, Hulette C, Rosenberg C, Otten U (1998). Decreased trkA neurotrophin receptor expression in the parietal cortex of patients with Alzheimer’s disease. Neurosci Lett, 241:151-154.
[202] Ferreira D, Westman E, Eyjolfsdottir H, Almqvist P, Lind G, Linderoth B, et al. (2015). Brain changes in Alzheimer’s disease patients with implanted encapsulated cells releasing nerve growth factor. J Alzheimers Dis, 43:1059-1072.
[203] Eriksdotter Jonhagen M, Nordberg A, Amberla K, Backman L, Ebendal T, Meyerson B, et al. (1998). Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease. Dement Geriatr Cogn Disord, 9:246-257.
[204] NCT02484547 (2015). A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer’s Disease.
[205] NCT02670083 (2016). A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy And Safety Study of Crenezumab in Patients With Prodromal to Mild Alzheimer’s Disease.
[206] NCT02051608 (2014). A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Efficacy and Safety Study of Gantenerumab in Patients With Mild Alzheimer’s Disease; Part II: Open-Label Extension For Participating Patients.
[207] NCT02008357 (2014). Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4 Study).
[208] Kozin SA, Barykin EP, Mitkevich VA, Makarov AA (2018). Anti-amyloid Therapy of Alzheimer’s Disease: Current State and Prospects. Biochemistry (Mosc), 83:1057-1067.
[209] Du QS, Xie NZ, Huang RB (2015). Recent development of peptide drugs and advance on theory and methodology of peptide inhibitor design. Med Chem, 11:235-247.
[210] Cho PY, Joshi G, Johnson JA, Murphy RM (2014). Transthyretin-derived peptides as beta-amyloid inhibitors. ACS Chem Neurosci, 5:542-551.
[211] Parthsarathy V, McClean PL, Holscher C, Taylor M, Tinker C, Jones G, et al. (2013). A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1DeltaE9 mouse model of Alzheimer’s disease. PLoS One, 8:e54769.
[212] Wang Q, Liang G, Zhang M, Zhao J, Patel K, Yu X, et al. (2014). De novo design of self-assembled hexapeptides as beta-amyloid (Abeta) peptide inhibitors. ACS Chem Neurosci, 5:972-981.
[213] Mo JJ, Li JY, Yang Z, Liu Z, Feng JS (2017). Efficacy and safety of anti-amyloid-beta immunotherapy for Alzheimer’s disease: a systematic review and network meta-analysis. Ann Clin Transl Neurol, 4:931-942.
[214] Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, et al. (2003). Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology, 61:46-54.
[215] DiFrancesco JC, Longoni M, Piazza F (2015). Anti-Abeta Autoantibodies in Amyloid Related Imaging Abnormalities (ARIA): Candidate Biomarker for Immunotherapy in Alzheimer’s Disease and Cerebral Amyloid Angiopathy. Front Neurol, 6:207.
[216] Radde R, Duma C, Goedert M, Jucker M (2008). The value of incomplete mouse models of Alzheimer’s disease. Eur J Nucl Med Mol Imaging, 35 Suppl 1:S70-74.
[217] Gozes I (2010). Tau pathology and future therapeutics. Curr Alzheimer Res, 7:685-696.
[218] NCT02579252 (2016). A 24 Months Randomised, Placebo-controlled, Parallel Group, Double Blinded, Multi Centre, Phase 2 Study to Assess Safety and Efficacy of AADvac1 Applied to Patients With Mild Alzheimer’s Disease.
[219] NCT02880956 (2016). A Phase 2 Multiple Dose, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ABBV-8E12 in Subjects With Early Alzheimer’s Disease.
[220] NCT03352557 (2018). Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Safety, Tolerability, and Efficacy of BIIB092 in Subjects With Mild Cognitive Impairment Due to Alzheimer’s Disease or With Mild Alzheimer’s Disease.
[221] NCT03518073 (2018 ). Assessment of Safety, Tolerability, and Efficacy of LY3303560 in Early Symptomatic Alzheimer’s Disease.
[222] NCT02380573 (2015). Cognitive and Functional Connectivity Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer’s Disease.
[223] NCT03446001 (2018). Randomized, Double-Blind, Placebo-Controlled, Three-Arm, 9-Month, Brain Imaging and Safety and Efficacy Study of TRx0237 in Subjects With Early Alzheimer’s Disease.
[224] Perez Ortiz JM, Swerdlow RH (2019). Mitochondrial dysfunction in Alzheimer’s disease: Role in pathogenesis and novel therapeutic opportunities. Br J Pharmacol.
[225] Sabbagh MN, Shill HA (2010). Latrepirdine, a potential novel treatment for Alzheimer’s disease and Huntington’s chorea. Curr Opin Investig Drugs, 11:80-91.
[226] Sweetlove M (2012). Phase III CONCERT Trial of Latrepirdine. Pharm Med, 26:113-115.
[227] van Roon-Mom WMC, Roos RAC, de Bot ST (2018). Dose-Dependent Lowering of Mutant Huntingtin Using Antisense Oligonucleotides in Huntington Disease Patients. Nucleic Acid Ther, 28:59-62.
[228] NCT00440050 (2007). A Randomized Double-Blind Placebo-Controlled Trial Of The Effects Of Docosahexaenoic Acid (DHA) In Slowing The Progression Of Alzheimer’s Disease.
[229] NCT00235716 (2007). CSP #546 - A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer’s Disease (TEAM-AD).
[230] Jicha GA, Markesbery WR (2010). Omega-3 fatty acids: potential role in the management of early Alzheimer’s disease. Clin Interv Aging, 5:45-61.
[231] Cervantes B, Ulatowski LM (2017). Vitamin E and Alzheimer’s Disease-Is It Time for Personalized Medicine? Antioxidants(Basel), 6.
[232] NCT00151502 (2002). An 80-Week, Randomized, Multi-Center, Parallel-Group, Double-Blind Study of the Efficacy and Safety of Atorvastatin 80 MG Plus an Acetylcholinesterase Inhibitor Versus an Acetylcholinesterase Inhibitor Alone in the Treatment of Mild to Moderate Alzheimer’s Disease.
[233] NCT00053599 (2002). A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial of Simvastatin to Slow the Progression of Alzheimer’s Disease.
[234] McGuinness B, Passmore P (2010). Can statins prevent or help treat Alzheimer’s disease? J Alzheimers Dis, 20:925-933.
[235] Xiao S Zhang Z, Geng M, GV-971 Study Group (2018). Phase 3 Clinical Trial of a Novel and Multi-targeted Oligosaccharide in Patients with Mild-moderate AD in China. Clinical Trials on Alzheimer’s Disease.
[236] NCT03715114 (2018). A Study to Assess the Safety and Pharmacokinetics of Oral Sodium Oligo-mannurarate (GV-971) in Healthy Chinese Subjects.
[237] Oules B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, et al. (2012). Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci, 32:11820-11834.
[238] Huang SM, Mouri A, Kokubo H, Nakajima R, Suemoto T, Higuchi M, et al. (2006). Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function. J Biol Chem, 281:17941-17951.
[239] Van Dam D, D'Hooge R, Staufenbiel M, Van Ginneken C, Van Meir F, De Deyn PP (2003). Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci, 17:388-396.
[240] Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, et al. (2000). A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Nature, 408:975-979.
[241] Escribano L, Simon AM, Perez-Mediavilla A, Salazar-Colocho P, Del Rio J, Frechilla D (2009). Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer’s disease mouse model. Biochem Biophys Res Commun, 379:406-410.
[242] Palop JJ, Jones B, Kekonius L, Chin J, Yu GQ, Raber J, et al. (2003). Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits. Proc Natl Acad Sci U S A, 100:9572-9577.
[243] Ambree O, Richter H, Sachser N, Lewejohann L, Dere E, de Souza Silva MA, et al. (2009). Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer’s disease. Neurobiol Aging, 30:1192-1204.
[244] Kosel F, Torres Munoz P, Yang JR, Wong AA, Franklin TB (2019). Age-related changes in social behaviours in the 5xFAD mouse model of Alzheimer’s disease. Behav Brain Res, 362:160-172.
[245] Ohno M, Chang L, Tseng W, Oakley H, Citron M, Klein WL, et al. (2006). Temporal memory deficits in Alzheimer’s mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci, 23:251-260.
[246] Hanzel CE, Pichet-Binette A, Pimentel LS, Iulita MF, Allard S, Ducatenzeiler A, et al. (2014). Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer’s disease. Neurobiol Aging, 35:2249-2262.
[247] Heggland I, Storkaas IS, Soligard HT, Kobro-Flatmoen A, Witter MP (2015). Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer’s disease. Eur J Neurosci, 41:1245-1262.
[1] Wenbo Li,Ling Kui,Tsirukis Demetrios,Xun Gong,Min Tang. A Glimmer of Hope: Maintain Mitochondrial Homeostasis to Mitigate Alzheimer’s Disease[J]. Aging and disease, 2020, 11(5): 1260-1275.
[2] Kan Yin Wong,Jaydeep Roy,Man Lung Fung,Boon Chin Heng,Chengfei Zhang,Lee Wei Lim. Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease[J]. Aging and disease, 2020, 11(5): 1291-1316.
[3] Wei-Xing Ma,Jing Tang,Zhi-Wen Lei,Chun-Yan Li,Li-Qing Zhao,Chao Lin,Tao Sun,Zheng-Yi Li,Ying-Hui Jiang,Jun-Tao Jia,Cheng-Zhu Liang,Jun-Hong Liu,Liang-Jun Yan. Potential Biochemical Mechanisms of Brain Injury in Diabetes Mellitus[J]. Aging and disease, 2020, 11(4): 978-987.
[4] Seong Gak Jeon, Anji Yoo, Dong Wook Chun, Sang Bum Hong, Hyunju Chung, Jin-il Kim, Minho Moon. The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis[J]. Aging and disease, 2020, 11(3): 705-724.
[5] Xiaoheng Li, Yajin Liao, Yuan Dong, Shuoshuo Li, Fengchao Wang, Rong Wu, Zengqiang Yuan, Jinbo Cheng. Mib2 Deficiency Inhibits Microglial Activation and Alleviates Ischemia-Induced Brain Injury[J]. Aging and disease, 2020, 11(3): 523-535.
[6] Yongming Jia, Na Wang, Yingbo Zhang, Di Xue, Haoming Lou, Xuewei Liu. Alteration in the Function and Expression of SLC and ABC Transporters in the Neurovascular Unit in Alzheimer’s Disease and the Clinical Significance[J]. Aging and disease, 2020, 11(2): 390-404.
[7] Yanfang Zhao, Yuan Zhang, Lei Zhang, Yanhan Dong, Hongfang Ji, Liang Shen. The Potential Markers of Circulating microRNAs and long non-coding RNAs in Alzheimer's Disease[J]. Aging and disease, 2019, 10(6): 1293-1301.
[8] Jie Zhang, Lijun Wang, Xia Deng, Guoqiang Fei, Lirong Jin, Xiaoli Pan, Liuhan Cai, Anthony D Albano, Chunjiu Zhong. Five-Minute Cognitive Test as A New Quick Screening of Cognitive Impairment in The Elderly[J]. Aging and disease, 2019, 10(6): 1258-1269.
[9] Piotr Gronek, Stefan Balko, Joanna Gronek, Adam Zajac, Adam Maszczyk, Roman Celka, Agnieszka Doberska, Wojciech Czarny, Robert Podstawski, Cain C. T Clark, Fang Yu. Physical Activity and Alzheimer’s Disease: A Narrative Review[J]. Aging and disease, 2019, 10(6): 1282-1292.
[10] Yingnan Xue, Zhenhua Zhang, Caiyun Wen, Huiru Liu, Suyuan Wang, Jiance Li, Qichuan Zhuge, Weijian Chen, Qiong Ye. Characterization of Alzheimer’s Disease Using Ultra-high b-values Apparent Diffusion Coefficient and Diffusion Kurtosis Imaging[J]. Aging and disease, 2019, 10(5): 1026-1036.
[11] Chun-Sheng Yang, Ai Guo, Yulin Li, Kaibin Shi, Fu-Dong Shi, Minshu Li. Dl-3-n-butylphthalide Reduces Neurovascular Inflammation and Ischemic Brain Injury in Mice[J]. Aging and disease, 2019, 10(5): 964-976.
[12] Xiao-Li Zhou, Meng-Bei Xu, Ting-Yu Jin, Pei-Qing Rong, Guo-Qing Zheng, Yan Lin. Preclinical Evidence and Possible Mechanisms of Extracts or Compounds from Cistanches for Alzheimer’s Disease[J]. Aging and disease, 2019, 10(5): 1075-1093.
[13] Zhi-Ying Tian, Chun-Yan Wang, Tao Wang, Yan-Chun Li, Zhan-You Wang. Glial S100A6 Degrades β-amyloid Aggregation through Targeting Competition with Zinc Ions[J]. Aging and disease, 2019, 10(4): 756-769.
[14] Takehiko Yamanaka, Yuto Uchida, Keita Sakurai, Daisuke Kato, Masayuki Mizuno, Toyohiro Sato, Yuta Madokoro, Yuko Kondo, Ayuko Suzuki, Yoshino Ueki, Fumiyasu Ishii, Cesar V Borlongan, Noriyuki Matsukawa. Anatomical Links between White Matter Hyperintensity and Medial Temporal Atrophy Reveal Impairment of Executive Functions[J]. Aging and disease, 2019, 10(4): 711-718.
[15] Yu-Sheng Li, Zhi-Hua Yang, Yao Zhang, Jing Yang, Dan-Dan Shang, Shu-Yu Zhang, Jun Wu, Yan Ji, Lu Zhao, Chang-He Shi, Yu-Ming Xu. Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer’s Disease[J]. Aging and disease, 2019, 10(4): 908-914.
Viewed
Full text


Abstract

Cited

  Shared   
Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail: editorial@aginganddisease.org
Powered by Beijing Magtech Co. Ltd