Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 7, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40478-019-0787-2
Keywords
alpha-Synuclein; Parkinson's disease; Lewy body dementia; Truncation; Amygdala; Inclusion formation; Neurodegeneration; Astrocyte; Lewy body
Categories
Funding
- National Institutes of Health [P50AG047266, R01NS089622, R01NS100876]
- [T32NS082168]
- [F30AG063446]
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The protein alpha-synuclein (alpha syn) forms pathologic aggregates in a number of neurodegenerative diseases including Lewy body dementia (LBD) and Parkinson's disease (PD). It is unclear why diseases such as LBD may develop widespread alpha syn pathology, while in Alzheimer's disease with amygdala restricted Lewy bodies (AD/ALB) the alpha syn aggregates remain localized. The amygdala contains alpha syn aggregates in both LBD and in AD/ALB; to understand why alpha syn pathology continues to progress in LBD but not in AD/ALB, tissue from the amygdala and other regions were obtained from 14 cases of LBD, 9 cases of AD/ALB, and 4 controls for immunohistochemical and biochemical characterization. Utilizing a panel of previously characterized alpha syn antibodies, numerous unique pathologies differentiating LBD and AD/ALB were revealed; particularly the presence of dense neuropil alpha syn aggregates, astrocytic alpha syn, and alpha syn-containing dystrophic neurites within senile plaques. Within LBD, these unique pathologies were predominantly present within the amygdala. Biochemically, the amygdala in LBD prominently contained specific carboxy-truncated forms of alpha syn which are highly prone to aggregate, suggesting that the amygdala may be prone to initiate development of alpha syn pathology. Similar to carboxy-truncated alpha syn, it was demonstrated herein that the presence of aggregation prone A53T alpha syn is sufficient to drive misfolding of wild-type alpha syn in human disease. Overall, this study identifies within the amygdala in LBD the presence of unique strain-like variation in alpha syn pathology that may be a determinant of disease progression.
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