期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1864, 期 1, 页码 208-225出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2017.07.005
关键词
A beta catabolism; A beta enzymatic degradation; Targeted proteomic; Post-translational modifications
资金
- National Institute of Health [AG030539, AG044817, AG051266, NS050276, RR027990]
- Alzheimer's Association [ZEN-14-283969]
- BrightFocus Foundation [A2015275S]
- Brain and Body Donation Program of the Banner Sun Health Research Institute [NIH AG19610, NS072026]
- Brain and Body Donation Program of the Banner Sun Health Research Institute [Arizona Department of Health Services] (Arizona Alzheimer's Research Center) [211002]
- Brain and Body Donation Program of the Banner Sun Health Research Institute [Arizona Biomedical Research Commission] [4001, 0011, 05-901, 1001]
- Brain and Body Donation Program of the Banner Sun Health Research Institute [Michael J. Fox Foundation for Parkinson's Research]
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR027990] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U24NS072026, P30NS050276] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG030539, R21AG051266, R21AG044817, P30AG019610] Funding Source: NIH RePORTER
Extensive parenchymal and vascular A beta deposits are pathological hallmarks of Alzheimer's disease (AD). Besides classic full-length peptides, biochemical analyses of brain deposits have revealed high degree of A beta heterogeneity likely resulting from the action of multiple proteolytic enzymes. In spite of the numerous studies focusing in A beta, the relevance of N- and C-terminal truncated species for AD pathogenesis remains largely understudied. In the present work, using novel antibodies specifically recognizing A beta species N-terminally truncated at position 4 or C-terminally truncated at position 34, we provide a clear assessment of the differential topographic localization of these species in AD brains and transgenic models. Based on their distinct solubility, brain N- and C-terminal truncated species were extracted by differential fractionation and identified via immunoprecipitation coupled to mass spectrometry analysis. Biochemical/biophysical studies with synthetic homologues further confirmed the different solubility properties and contrasting fibrillogenic characteristics of the truncated species composing the brain A beta peptidome. A beta C-terminal degradation leads to the production of more soluble fragments likely to be more easily eliminated from the brain. On the contrary, N-terminal truncation at position 4 favors the formation of poorly soluble, aggregation prone peptides with high amyloidogenic propensity and the potential to exacerbate the fibrillar deposits, self-perpetuating the amyloidogenic loop. Detailed assessment of the molecular diversity of A beta species composing interstitial fluid and amyloid deposits at different disease stages, as well as the evaluation of the truncation profile during various pharmacologic approaches will provide a comprehensive understanding of the still undefined contribution of A beta truncations to the disease pathogenesis and their potential as novel therapeutic targets.
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