Abstract
Small heat shock proteins (sHsps) are professional chaperones that have a specific function in helping the normal folding process of proteins and in the intracellular handling of misfolded proteins. The pathological lesions of Alzheimer's disease (AD), such as senile plaques (SPs) and cerebrovascular amyloid angiopathy (CAA), are characterized by the accumulation of the amyloid-beta protein. This accumulation of amyloid-beta in SPs results in degeneration of neurons, whereas this accumulation of amyloid-beta in CAA results in degeneration of cerebrovascular cells. We investigated the distribution of sHsps in AD brain. We observed that several members of the sHsp family colocalize with amyloid-beta in both SPs and CAA. In addition, we demonstrated that several sHsps directly bind amyloid-beta and regulate the accumulation of amyloid-beta in vitro. Furthermore, we demonstrated that sHsps, such as alpha-B-crystallin and Hsp20, inhibit amyloid-beta-mediated cytotoxicity towards cerebrovascular cells. The second part of the thesis describes the role of apolipoprotein E (apoE) and the low-density lipoprotein receptor related protein-1 (LRP-1) in amyloid-beta-mediated cell death of cerebrovascular cells. We observed that the degree of amyloid-beta-mediated toxicity of cerebrovascular cells is dependent on the apoE genotype of the cells, and that apoE causes a direct concentration-dependent inhibition of amyloid-beta-mediated toxicity towards these cells. In addition, we demonstrated that the amyloid-beta-mediated toxicity towards cerebrovascular cells is regulated by the uptake of amyloid-beta cells via the LRP-1 receptor. In the last part of the thesis, we summarize and discuss the role of chaperones, such as sHsps and apoE, in the pathogenesis of AD and propose future research plans.
