Distinctive alteration of presynaptic proteins in the outer molecular layer of the dentate gyrus in Alzheimer’s disease

Abstract

Synaptic degeneration has been reported as one of the best pathological correlate of cognitive deficit in Alzheimer’s Disease (AD). However, the location of these synaptic alterations within hippocampal sub-regions, the vulnerability of the presynaptic versus postsynaptic compartments, and the biological mechanisms for these impairments remain unknown. Here, we performed immunofluorescence labeling of different synaptic proteins in fixed and paraffin embedded human hippocampal sections and report reduced levels of several presynaptic proteins of the neurotransmitter release machinery (complexin-1, syntaxin-1A, synaptotagmin-1 and synaptogyrin-1) in AD cases. The deficit was restricted to the outer molecular layer (OML) of the dentate gyrus whereas other hippocampal sub-fields were preserved. Interestingly, standard markers of postsynaptic densities (SHANK2) and dendrites (MAP2) were unaltered, as well as the relative number of granule cells in the dentate gyrus, indicating that the deficit is preferentially presynaptic. Notably, staining for the axonal components, myelin basic protein, SMI-312 and Tau, was unaffected, suggesting that the local presynaptic impairment does not result from axonal loss or alterations of structural proteins of axons. There was no correlation between the reduction in presynaptic proteins in OML and the extent of the amyloid load or of the dystrophic neurites expressing phosphorylated forms of Tau. Altogether, this study highlights the distinctive vulnerability of the OML of dentate gyrus and supports the notion of presynaptic failure in AD.

APP accumulates with presynaptic proteins around amyloid plaques: A role for presynaptic mechanisms in Alzheimer's disease?

“…Indeed, the genetic deletion, or the loss of function of several presynaptic proteins (e.g., Munc18, α-synuclein, syntaxin1, or SNAP-25) leads to neurodegeneration. [43][44][45][46] Our observation of the selective accumulation of presynaptic proteins in APP accumulations contrasts with recent discoveries from us and others of broad downregulation of presynaptic proteins in AD brains [29][30][31][32] and indicates that the alteration of presynaptic proteins in AD is spatially heterogeneous. In the AD hippocampus, APP follows a complex pattern of misdistribution, too, accumulating within neuropil areas, and vanishing in neuronal somata where APP is normally prominent.…”

“…For example, we have reported that deletion of presenilin, the protease responsible for the production of Aβ peptide from APP cleavage, markedly decreases the abundance of synaptotagmin‐7, a key calcium sensor involved in presynaptic plasticity 29 . We and others have also reported downregulation of presynaptic proteins in AD brains 30–32 including proteins determinant of cognitive reserve like complexin‐1 33,34 . This collection of data has led us to advocate for the hypothesis of presynaptic failure in AD 35 .…”