Aging and Disease Volume 3 (2), 141-155; April 2012 [Epub: 2011, July 28 ]

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Original article

Amyloid Deposition and Advanced Age Fails to Induce Alzheimer’s Type Progression in a Double Knock-In Mouse Model

Gauri H. Malthankar-Phatak¹, Yin-Guo Lin¹, Nicholas Giovannone¹, Robert Siman^1,2,*

¹Department of Neurosurgery, University of Pennsylvania School of Medicine, and ²Center for Brain Injury and Repair, University of Pennsylvania, Philadelphia, PA, USA

[Received July 15, 2011; Revised July 25, 2011; Accepted July 25, 2011]

ABSTRACT: It has been challenging to develop transgenic and gene-targeted mouse models that recapitulate all of the neuropathological features of Alzheimer’s disease (AD). For example, in the APP/PS-1 double knock-in mutant mouse (DKI), frank neurodegeneration is not observed at middle age and synapse loss is pronounced only within amyloid plaques. Here, we investigated whether continued amyloid deposition and advanced age of 24-27 months lead to loss of neurons and synapses, tau hyperphosphorylation, and other pathological features of AD. We focused on the perforant pathway projection from entorhinal cortex to hippocampal dentate gyrus, since it is preferentially impacted by plaques, tangles, and neuronal loss early in the course of AD. Compared with wild type controls matched for age and gender, expression of neither reelin nor NeuN was altered in the entorhinal layer 2 neurons of origin. Retrograde labeling of the perforant pathway with Fluorogold indicated no cell loss, axonal atrophy, or nerve terminal degeneration. The lack of neuronal loss or atrophy was confirmed by volumetric analysis of the ventral dentate gyrus and immunostaining for a synaptic marker. We also searched for other hallmarks of AD neuropathology by labeling for hyperphosphorylated pre-tangle tau, accumulation of cathepsin D-containing autolysosomes, and cyclin A-positive neurons aberrantly re-entering the cell cycle. None of these AD pathologies were observed in the entorhinal cortex, dentate gyrus, or any other forebrain region. Our results indicate that the DKI mouse does not show appreciable Alzheimer-type disease progression, even at advanced age and in the phase of over 18 months of robust cerebral amyloid deposition. The insufficiency of amyloid deposition to induce other AD-type neuropathologies and neurodegeneration in the aging mouse brain suggests an important role for tauopathy or other factors for triggering the pathogenesis of AD.

Key words: Amyloid; aging; neuronal degeneration; Alzheimer’s disease; tau; cathepsin D