Abstract
Alzheimer’s disease is caused by increased production or reduced clearance of amyloid-β, which results in the formation amyloid-β plaques and triggers a cascade of downstream events leading to progressive neurodegeneration. The earliest clinical symptoms of Alzheimer’s disease, i.e., memory loss, are however poorly understood from a molecular and cellular perspective. Here we used APPswe/PS1dE9 (APP/PS1) transgenic mice to study the early pre-pathological effects of increased amyloid-β levels on hippocampal synaptic plasticity and memory. Using an unbiased proteomics approach we show that the early increase in amyloid-β levels in APP/PS1 mice at three months of age coincides with a robust and significant upregulation of several protein components of the extracellular matrix in hippocampal synaptosome preparations. This increase in extracellular matrix levels occurred well before the onset of plaque formation and was paralleled by impairments in hippocampal long-term potentiation and contextual memory. Direct injection into the hippocampus of the extracellular matrix inactivating enzyme chondroitinase ABC restored both long-term potentiation and contextual memory performance. These findings indicate an important role for the extracellular matrix in causing early memory loss in Alzheimer’s disease.
Highlights
Alzheimer’s disease (AD) is characterized by progressive cognitive decline, with memory loss being one of the earliest clinical symptoms
We evaluated hippocampal memory in 3 months old amyloid precursor protein (APP)/PS1 mice that lack AD-like pathology
When we tested spatial memory performance in a Morris water maze task using a separate batch of animals, no differences were observed between APP/PS1 mice and wildtype littermates at 4 months of age; wildtype and transgenic animals performed well, both during the 5-day training (Figure 2d) and in the probe trial (Figure 2e-f )
Summary
Alzheimer’s disease (AD) is characterized by progressive cognitive decline, with memory loss being one of the earliest clinical symptoms. The earliest neuropathological changes in AD are consistently observed in the medial temporal lobe (entorhinal cortex and hippocampus) [6], and hippocampal volume loss is the best established diagnostic marker for AD and highly predictive of disease progression [7]. Deficits in hippocampal memory performance and synaptic plasticity have been established in various animal models of AD, before neuropathological changes are observed and in the absence of neurodegeneration [8,9]. Hippocampal synaptic dysfunction most likely underlies initial memory deficits in AD and may trigger further disease progression [10,11,12,13]
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