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Knockout of apolipoprotein A‐I decreases parenchymal and vascular β‐amyloid pathology in the Tg2576 mouse model of Alzheimer's disease

Contu, Laura; Carare, Roxana O. and Hawkes, Cheryl A. (2019). Knockout of apolipoprotein A‐I decreases parenchymal and vascular β‐amyloid pathology in the Tg2576 mouse model of Alzheimer's disease. Neuropathology and Applied Neurobiology (Early Access).

DOI (Digital Object Identifier) Link: https://doi.org/10.1111/nan.12556
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Abstract

Aims
Apolipoprotein A‐I (apoA‐I), the principal apolipoprotein associated with high density lipoproteins (HDL) in the periphery, is also found at high concentrations in the cerebrospinal fluid. Previous studies have reported either no impact or vascular‐specific effects of apoA‐I knockout on β‐amyloid (Aβ) pathology. However, the putative mechanism(s) by which apoA‐I may influence Aβ deposition is unknown.

Methods
We evaluated the effect of apoA‐I deletion on Aβ pathology, Aβ production and clearance from the brain in the Tg2576 mouse model of AD.

Results
Contrary to previous reports, deletion of the APOA1 gene significantly reduced concentrations of insoluble Aβ40 and Aβ42 and reduced plaque load in both the parenchyma and blood vessels of apoA‐I knockout x Tg2576 mice compared to Tg2576 animals. This was not due to decreased Aβ production or alterations in Aβ species. Levels of soluble clusterin/apoJ were significantly higher in neurons of apoA‐I KO mice compared to both wildtype and apoA‐I KO x Tg2576 mice. In addition, clearance of Aβ along intramural periarterial drainage pathways was significantly higher in apoA‐I KO mice compared to wildtype animals.

Conclusion
These data suggest that deletion of apoA‐I is associated increased clearance of Aβ and reduced parenchymal and vascular Aβ pathology in the Tg2576 model. These results suggest that peripheral dyslipidaemia can modulate the expression of apolipoproteins in the brain and may influence Aβ clearance and aggregation in AD.

Item Type: Journal Item
Copyright Holders: 2019 British Neuropathological Society
ISSN: 1365-2990
Keywords: Apolipoprotein A-I; Clusterin; mice; Knockout; plaque; Amyloid; Lipoproteins; Nervous System
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 60688
SWORD Depositor: Jisc Publications-Router
Depositing User: Jisc Publications-Router
Date Deposited: 30 Apr 2019 09:05
Last Modified: 11 Nov 2019 14:13
URI: http://oro.open.ac.uk/id/eprint/60688
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