Quantitative Neuropathology in Alzheimer's Mouse Models

摘要

Transgenic (Tg) mouse models of Alzheimer's Disease (AD) provide insight into the earliest changes observable as potential strategic targets by which to mount therapeutic interventions. A comparison of the different mouse models to determine the earliest time at which diffuse or compact amyloid deposits are detected versus other structural pathology indicates that multiple factors combine to produce highly variable courses across Tg mouse models. Therefore, we sought to define the earliest tune point at which alterations couldbe detected and whether such changes were progressive in two different mouse models, the Elan PDAPP mouse and the original Tg2576 mouse. In the Elan PDAPP mouse, Tg hippocampal volumes were statistically significantly smaller at 100 days but the volume differences did not progress. Furthermore, the volume loss was restricted to the dentate gyrus (DG), where the difference between Tg and wild-type (WT) brain was nearly 30% by 100 days. Amyloid deposition was not detected until six months of age. Subsequent studies confirmed that the outer molecular layer (OML) terminal projections of the lateral entorhinal cortex layer II neurons were the earliest and most consistent sites of synaptic dysfunction. With age, PDAPP WT mice eventually also showed loss of OML dendritic spines. In the Tg2576 mice, no hippocampal or cortical volumetric differences were detected, but OML dendritic spine analysis, electrophysiology and behavior were all affected (versus WT mice) by four months of age. Amyloid was not detectable until 15 months of age. Others have recently confirmed these observations on the dentate OML synapse loss in the older Tg2576 mouse. Thus, early neurotoxic fragments may make highly vulnerable synapses the earliest site pathology in these simulations of familial AD.