[P1–183]: Loss of Clusterin Shifts Amyloid Deposition to the Cerebrovasculature via Disruption of Perivascular Drainage Pathways

Abstract

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide deposition in brain parenchyma as plaques and in cerebral blood vessels as cerebral amyloid angiopathy (CAA). CAA deposition leads to several clinical complications, including intracerebral hemorrhage. The underlying molecular mechanisms that regulate plaque and CAA deposition in the vast majority of sporadic AD patients remain unclear. The clusterin (CLU) gene is genetically associated with AD and CLU has been shown to alter aggregation, toxicity, and bloodbrain barrier transport of Aβ, suggesting it might play a key role in regulating the balance between Aβ deposition and clearance in both brain and blood vessels. Here, we investigated the effect of CLU on Aβ pathology using the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD amyloidosis on a Clu +/+ or Clu −/− background. We found a marked decrease in plaque deposition in the brain parenchyma but an equally striking increase in CAA within the cerebrovasculature of APP/PS1;Clu −/− mice. Surprisingly, despite the several-fold increase in CAA levels, APP/PS1;Clu −/− mice had significantly less hemorrhage and inflammation. Mice lacking CLU had impaired clearance of Aβ in vivo and exogenously added CLU significantly prevented Aβ binding to isolated vessels ex vivo. These findings suggest that in the absence of CLU, Aβ clearance shifts to perivascular drainage pathways, resulting in fewer parenchymal plaques but more CAA because of loss of CLU chaperone activity, complicating the potential therapeutic targeting of CLU for AD.

Topical Cellular/Tissue and Molecular Aspects Regarding Nonpharmacological Interventions in Alzheimer’s Disease—A Systematic Review

“…The mechanism by which ApoE exerts its effects on Aβ transport and deposition is unclear, but it seems to be related to a worsening of the clearance of Aβ [28,61]. On the other hand, clusterin (apolipoprotein J) appears to be involved in blocking the aggregation of Aβ and preventing its deposition [62].…”