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- W1999297988 abstract "Increasing evidence favors the synapse as an initial site of neuronal damage by amyloid ß-protein (Aß) and such synaptic damage is thought to underlie the cognitive deficits seen in Alzheimer's disease (AD). Among the many proposed pathways of Aß toxicity, our study addresses the potential involvement of APP in Aß-initiated synaptic damage. Previous studies have suggested that Aß-induced cell death is attenuated in the absence of APP. Further, this effect of APP may, in part, be mediated by cleavage of APP in the cytosolic domain following an aspartate residue at position 664 (APP695 numbering) by caspases or caspase-like proteases, leading to the release of C31 peptide. However, virtually all the cell-based studies assessed cell death and support for this mechanism in Aß-induced loss of synapses has not been rigorously tested. Initial studies from our lab showed that primary hippocampal neurons cultured from APP deficient neurons were protected from Aß mediated synapse loss. Consistent with this observation, primary neurons cultured from transgenic mice expressing the APP D664A construct did not demonstrate any reduction in dendritic spine density as compared to neurons from similar APP transgenic mice without the D664A mutation. To test our hypothesis that cleavage of APP at position D664 contributes to synaptic dysfunction and synapse loss, we directly compared the physiological consequences of expression of APP with or without the D664A mutation. Previously, the Malinow lab had shown that expression of the APP C-terminal fragment (C99) resulted in reduction in NMDA and AMPA mediated currents, concomitant with loss of dendritic spines, that were shown to be due to Aß production. Consistent with this hypothesis, our initial results showed that neurons expressing the APP C99 fragment containing the D664A mutation did not demonstrate any impairments in NMDA or AMPA currents as compared to the wild type C99 construct. Ongoing studies are focusing on whether structural correlates, (i.e. preservation in dendritic spines), accompany these electrophysiological changes. Thus, it appeared that the cytosolic domain of APP contributes to Aß-induced synaptic depression. However, it remains to be established how APP contributes to synaptic injury in the context of other proposed pathways of Aß toxicity." @default.
- W1999297988 created "2016-06-24" @default.
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- W1999297988 date "2011-07-01" @default.
- W1999297988 modified "2023-09-27" @default.
- W1999297988 title "P3-226: Elimination of APP caspase cleavage site D664 attenuates Aβ-mediated synaptic depression" @default.
- W1999297988 doi "https://doi.org/10.1016/j.jalz.2011.05.1668" @default.
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