Selective deposition of amyloid-? protein in the entorhinal-dentate projection of a transgenic mouse model of alzheimer's disease

Abstract

Early and selective deposition of amyloid beta protein(Abeta) is thought to be a pathological feature central to Alzheimer's disease (AD). It has been a great challenge to identify the mechanism(s) responsible for the selectivity of Abeta deposition and the deposition into a temporal sequence of the pathogenesis in this disorder. We now report that the transgenic mouse (PDAPP), which overexpresses the human amyloid precursor protein containing the familial AD mutation (APP717V-F), develops brain region-specific Abeta deposits along with some pathologies associated with AD. By using monoclonal antibodies that recognize multiple sites on the human Abeta peptide, we show that Abeta deposits are localized primarily to the entorhinal cortex and hippocampal/dentate gyrus regions. Abeta deposition exhibited consistent laminar distribution throughout the hippocampal formation that was confined mostly to a dense terminal field in the outer portion of the stratum moleculare of the dentate gyrus and the stratum lacunosum of the hippocampus proper of 13-month-old heterozygous PDAPP mice. Abeta deposits were also observed in the supragranular zone of the dentate gyrus. Similarly, laminar distribution of Abeta deposits were evident in the entorhinal cortex, most notably in the molecular layer and in laminar layer II-III. The defined laminar pattern of the Abeta deposition, which resembles that of AD, suggests that intrinsic factors in the perforant path, the major projection from the entorhinal cortex to the hippocampal formation, and their respective local paths contribute, at least in part, to the extracellular Abeta deposition in the transgenic mouse model of AD.

Reduced Spine Density in Specific Regions of CA1 Pyramidal Neurons in Two Transgenic Mouse Models of Alzheimer's Disease

“…There are several possible explanations for such selective loss of spines in young APP transgenic mice. First, soluble A␤ is generated at higher concentration in stratum oriens compared with stratum radiatum and stratum lacunosum-moleculare (Buxbaum et al, 1998;Su and Ni, 1998;Lazarov et al, 2002;Reilly et al, 2003) Second, a general A␤ overproduction may target specific cell types especially relevant for local network rearrangement, i.e., GABAergic interneurons. On the apical side, CA1 pyramidal neurons receive synaptic input from Schaffer collaterals proximal to the soma and from the entorhinal cortex (via the perforant path) on distal dendrites, whereas the basal dendrites receive most synaptic input from Schaffer collaterals (Spruston and McBain, 2007).…”

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

“…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).…”