Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer’s disease

Abstract

Progressive accumulation of Alzheimer's disease-related pathology is associated with cognitive dysfunction. Differences in cognitive reserve may contribute to individual differences in cognitive function in the presence of comparable neuropathology. The protective effects of cognitive reserve could contribute differentially in early versus late stages of the disease. We investigated presynaptic proteins as measures of brain reserve (a subset of total cognitive reserve), and used Braak staging to estimate the progression of Alzheimer's disease. Antemortem evaluations of cognitive function, postmortem assessments of pathologic indices, and presynaptic protein analyses, including the complexins I and II as respective measures of inhibitory and excitatory terminal function, were assayed in multiple key brain regions in 418 deceased participants from a community study. After covarying for demographic variables, pathologic indices, and overall synapse density, lower brain complexin-I and -II levels contributed to cognitive dysfunction (P < 0.01). Each complexin appeared to be dysregulated at a different Braak stage. Inhibitory complexin-I explained 14.4% of the variance in global cognition in Braak 0-II, while excitatory complexin-II explained 7.3% of the variance in Braak V-VI. Unlike other presynaptic proteins, complexins did not colocalize with pathologic tau within neuritic plaques, suggesting that these functional components of the synaptic machinery are cleared early from dystrophic neurites. Moreover, complexin levels showed distinct patterns of change related to memory challenges in a rat model, supporting the functional specificity of these proteins. The present results suggest that disruption of inhibitory synaptic terminals may trigger early cognitive impairment, while excitatory terminal disruption may contribute relatively more to later cognitive impairment.

Religious Orders Study and Rush Memory and Aging Project

“…However, one can be more or less resilient relative to the average person and therefor have a slower or faster rate of residual cognitive decline. We found several genomic and neurobiologic indices of resilience were associated with a slower rate of decline including presynaptic proteins, neuron density, and BDNF expression [122, 132–137]. We are also finding genes associated with a faster rate of cognitive decline [138].…”

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

“…1). Ramos-Miguel et al have also detected higher levels of CPLX1 in the OML than in the IML [37]. Albeit both IML and OML contains mainly excitatory inputs to GC, the afferent input is, to a large extent distinct and arises from mossy cells of the CA4 (called associational/commissural projections) and EC layer II, respectively.…”

Extra virgin olive oil improves synaptic activity, short‐term plasticity, memory, and neuropathology in a tauopathy model

“…CPLX1 is a presynaptic protein known as SNARE complex‐binding protein which plays an important role in vesicle release promoting synchronization of Ca 2+ triggered vesicle fusion and inhibiting spontaneous vesicles release (Lai et al, ). Downregulation of CPLX1 is associated with impaired basal synaptic strength and short‐term plasticity (Chang et al, ), and more recently decreased CPLX1 levels have been suggested as a significant risk factor associated with AD and Parkinson's disease (Lahut et al, ; Ramos‐Miguel et al, ). Our results further support the importance of CPLX1 for the maintenance of basal synaptic activity and short‐term plasticity and provide new evidence on the involvement of this protein in neurodegenerative disorders associated with tau pathology.…”