Amyloid deposition in the hippocampus and entorhinal cortex: Quantitative analysis of a transgenic mouse model

Abstract

Various transgenic mouse models of Alzheimer's disease (AD) have been developed that overexpress mutant forms of amyloid precursor protein in an effort to elucidate more fully the potential role of ␤-amyloid (A␤) in the etiopathogenesis of the disease. The present study represents the first complete 3D reconstruction of A␤ in the hippocampus and entorhinal cortex of PDAPP transgenic mice. A␤ deposits were detected by immunostaining and thioflavin fluorescence, and quantified by using high-throughput digital image acquisition and analysis. Quantitative analysis of amyloid load in hippocampal subfields showed a dramatic increase between 12 and 15 months of age, with little or no earlier detectable deposition. Three-dimensional reconstruction in the oldest brains visualized previously unrecognized sheets of A␤ coursing through the hippocampus and cerebral cortex. In contrast with previous hypotheses, compact plaques form before significant deposition of diffuse A␤, suggesting that different mechanisms are involved in the deposition of diffuse amyloid and the aggregation into plaques. The dentate gyrus was the hippocampal subfield with the greatest amyloid burden. Sublaminar distribution of A␤ in the dentate gyrus correlated most closely with the termination of afferent projections from the lateral entorhinal cortex, mirroring the selective vulnerability of this circuit in human AD. This detailed temporal and spatial analysis of A␤ and compact amyloid deposition suggests that specific corticocortical circuits express selective, but late, vulnerability to the pathognomonic markers of amyloid deposition, and can provide a basis for detecting prior vulnerability factors. A lzheimer's disease (AD), the most common form of dementia in the aging population, is characterized by the extracellular accumulation of ␤-amyloid (A␤), the intracellular appearance of neurofibrillary tangles, and synaptic and neuronal loss (1). Mounting evidence supports a causal role for A␤ in the pathophysiology of AD (2, 3). Various transgenic models have been developed which overexpress mutant forms of amyloid precursor protein (APP); these models mimic some aspects of AD pathology, including A␤ deposition and synaptic damage (4-9).In AD, amyloid deposition and neurofibrillary tangle formation occur in a spatially and temporally defined pattern in specific neocortical and hippocampal regions that reflects selective vulnerability of certain circuits, particularly corticocortical circuits in neocortex (10, 11) and the perforant path that projects from the entorhinal cortex (EC) to the dentate gyrus (DG) (12, 13). Transgenic mouse models that overexpress mutant APP show an age-dependent accumulation of A␤ (14); however, there has been no comprehensive quantitative analysis of the spatial and temporal progression of amyloid and A␤ accumulation, especially in the most vulnerable regions.Deposits of A␤ that form in AD have been morphologically classified into several types, such as diffuse, fibrillar, dense-cored or classic, compact, or ''burnt-out'' ...

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

“…The molecular layer of the dentate gyrus is one of the first regions to show amyloid deposition and synapse loss in the Tg2576 mouse model of AD (Su and Ni, 1998;Reilly et al, 2003;Dong et al, 2007). However, it is difficult to know the implications of increases in synapse density after memantine administration in Tg2576 mice.…”

“…We focused our structural assessments on the hippocampal formation because these structures play a major role in learning and memory (Knowles, 1992;Bannerman et al, 2001) and is also a site for Ab deposition in AD patients (Probst et al, 1983;West et al, 2004) and in several transgenic mouse models of AD (Su and Ni, 1998;Reilly et al, 2003). Synapse loss induced by Ab remains a likely basis for the behavioral deficits observed in Tg2576 mice (Stern et al, 2004).…”

Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

“…In transgenic mouse models of AD, β-amyloid deposits have been classified as diffuse or compact, with compact deposits being more frequently associated with neuritic changes (Reilly et al, 2003). Recent studies have shown that soluble, low-molecularweight (8-24 kDa) Aβ oligomers, referred to as β-amyloid-derived diffusible ligands, may be capable of producing neuronal dysfunction (Lambert et al, 1998;Walsh et al, 2002;Gong et al, 2003;Mattson, 2004).…”

“…Also, they are primary sites for β-amyloid deposition in APP transgenic mice (Su and Ni, 1998;Reilly et al, 2003). The perforant path that projects from the entorhinal cortex to the dentate gyrus is among the most vulnerable pathways in cortex with respect to both aging and AD pathology Gazzaley et al, 1997).…”

Neuroscience-based Tests for Assessing Cognitive Changes in Normal Aging and in the Prodromal Phase of Alzheimer’s Disease

“…The value of biomarkers predicting conversion to clinical AD has limitations in the absence of tests sensitive to subtle cognitive changes in prodromal AD. Investigations using animal models of AD also indicate that the entorhinal cortex and perforant pathway input to the hippocampus are among the earliest affected and most vulnerable regions of Aβ pathology [29][30][31]. Spatial ability likely becomes affected in prodromal AD because Aβ selectively disrupts perforant pathway input to hippocampus from the entorhinal cortex.…”