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P1‐004: Lipidation in cortical synapses of Alzheimer's disease versus normal controls
Author(s) -
Gonzalez Bianca L.,
Gylys Karen H.,
Bilousova Tina
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.200
Subject(s) - apolipoprotein e , ldl receptor , cholesterol , lipoprotein , synaptosome , medicine , receptor , endocrinology , lipid metabolism , apolipoprotein b , chemistry , biology , biochemistry , disease , central nervous system
Background: The prevailing hypothesis of AD pathogenesis places amyloid-b oligomers upstream of tau pathology. Like AD, tau pathology is present in Parkinson’s disease (PD). However, asynuclein, which accumulates in Lewy bodies in PD and in many cases of AD as well, is considered the initiator of tau pathology in PD. In a healthy adult brain, neurons remain post-mitotic through tight regulation of their cell cycle machinery, but in AD and PD, cell cycle proteins are aberrantly activated, causing these normally quiescent neurons to re-enter the cell cycle. Neurons that re-enter the cell cycle progress at least into S-phase, and account for significant neuron death. Despite a large body of evidence demonstrating CCR in AD and PD,many questions regarding its underlyingmechanism remain unanswered. Previous work from our lab established that amyloid-b oligomers (AbOs) induce ectopic neuronal CCR through a mechanism dependent on tau phosphorylation at Y18, S409 and S416 (Seward, et al. 2013. J Cell Sci 126: 1278-1276). This project seeks to determine whether a-synuclein contributes to CCR in AD and PD. Methods: Primary mouse neurons treated with AbOs were used to model AD. Neurons were analyzed by immunoblotting and immunofluorescence. Results: AbOs stimulate a tau-dependent increase in endogenous a-synuclein. Overexpression of the pathogenic A53T, E46K, or A30P mutations of human a-synuclein induced ectopic neuronal CCR independently of AbOs, with the A30Pmutation generating the most robust response. In contrast, reduction of endogenous a-synuclein using shRNA ameliorates AbO-induced tau phosphorylation, and consequently prevents neuronal CCR. Conclusions: Taken together, these data implicate a-synuclein as a novel modulator of ectopic neuronal CCR in AD and PD.