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

Brain Communications (2021)

• Haytural, H., Jordà-Siquier, T., Winblad, B., Mulle, C., Tjernberg, L.O., Granholm, A.-C., Frykman, S., Barthet, G

Synaptic degeneration has been reported as one of the best pathological correlates of cognitive deficits in Alzheimer’s disease.
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 immuno-
fluorescence labelling 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 Alzheimer’s disease cases. The deficit was restricted to the outer molecular layer of the dentate gyrus,
whereas other hippocampal sub-fields were preserved. Interestingly, standard markers of postsynaptic densities (SH3 and multiple
ankyrin repeat domains protein 2) and dendrites (microtubule-associated protein 2) 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 compo-
nents, 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 pro-
teins in the outer molecular layer 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 outer molecular layer of the dentate gyrus and supports
the notion of presynaptic failure in Alzheimer’s disease.

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