Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways

• DOI: 10.1073/pnas.1701137114
• Publication Date: 2017-07-13T01:10:36Z
• Authors: Aleksandra M. Wojtas; Silvia S. Kang; Benjamin M. Olley; Maureen Gatherer; Mitsuru Shinohara; Patricia A. Lozano; Chia-Chen Liu; Aishe Kurti; Kelsey E. Baker; Dennis W. Dickson; Mei Yue; Leonard Petrucelli; Guojun Bu; Roxana O. Carare; John D. Fryer
• Keywords: 0301 basic medicine; 570; 610; Hemorrhage; Mice, Mutant Strains; 3. Good health; Amyloid beta-Protein Precursor; Cerebral Amyloid Angiopathy; Disease Models, Animal; Mice; 03 medical and health sciences; Clusterin; Alzheimer Disease; Animals; Cerebral amyloid angiopathy; Alzheimer’s disease; Aβ

Significance

Deposition of amyloid-β (Aβ) peptide in the form of parenchymal plaques and Aβ accumulation in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA) are pathological hallmarks of Alzheimer’s disease (AD). The clusterin ( CLU ) gene, which confers AD risk, is associated with amyloid deposition. Here we show that loss of CLU promotes cerebrovascular CAA, yet significantly reduces the amount of parenchymal plaques by altering perivascular drainage of Aβ in the APP/PS1 mouse model of AD. The absence of CLU in these mice is associated with a lower number of hemorrhages and a decrease in inflammation. These results suggest that CLU functions as a major Aβ chaperone to maintain Aβ solubility along interstitial fluid drainage pathways and prevent CAA formation.