Predominant loss of glutamatergic terminal markers in a β-amyloid peptide model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized phenotypically by memory impairment, neurochemically by accumulation of β-amyloid peptide (such as Aβ1–42) and morphologically by an initial loss of nerve terminals in cortical and hippocampal regions. However, it is not known what nerve terminals are mostly affected in early AD. We now used a mouse model of AD, based on the intra-cerebral administration of soluble Aβ1-42, that leads to memory impairment and loss of nerve terminal markers within 2 weeks, to investigate which type of hippocampal nerve terminals was mostly affected in the hippocampus. Western blot analysis revealed a decrease of the density of vesicular glutamate transporters type 1 (vGluT1, a marker of glutamatergic terminals; −20.1 ± 3.6%) and of vesicular acetylcholine transporters (vAChT, a marker of cholinergic terminals; −27.2 ± 0.9%) but not of vesicular GABA transporters (vGAT, a marker of GABAergic terminals) in the hippocampus of Aβ-injected mice. Immunocytochemical analysis of single hippocampal nerve terminals revealed that the decrease of the density of vGluT1 reflects a reduction of the number of vGluT1-immunopositive nerve terminals (−10.6 ± 3.6%), while no significant changes in the number of vAChT- or vGAT-immunopositive nerve terminals were observed. This pilot study shows that, in this Aβ-based model of AD, there is an asymmetric loss of different synaptic markers with a predominant susceptibility of glutamatergic synapses.This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.