Heat shock proteins and amateur chaperones in amyloid-Beta accumulation and clearance in Alzheimer's disease

Abstract

The pathologic lesions of Alzheimer's disease (AD) are characterized by accumulation of protein aggregates consisting of intracellular or extracellular misfolded proteins. The amyloid-beta (Abeta) protein accumulates extracellularly in senile plaques and cerebral amyloid angiopathy, whereas the hyperphosphorylated tau protein accumulates intracellularly as neurofibrillary tangles. "Professional chaperones", such as the heat shock protein family, have a function in the prevention of protein misfolding and subsequent aggregation. "Amateur" chaperones, such as apolipoproteins and heparan sulfate proteoglycans, bind amyloidogenic proteins and may affect their aggregation process. Professional and amateur chaperones not only colocalize with the pathological lesions of AD, but may also be involved in conformational changes of Abeta, and in the clearance of Abeta from the brain via phagocytosis or active transport across the blood-brain barrier. Thus, both professional and amateur chaperones may be involved in the aggregation, accumulation, persistence, and clearance of Abeta and tau and in other Abeta-associated reactions such as inflammation associated with AD lesions, and may, therefore, serve as potential targets for therapeutic intervention.

Fig. 1

The role of heat shock proteins (Hsp) and small heat shock proteins (sHsps) in recognition and refolding of unfolded and misfolded proteins. Unfolded or misfolded proteins are recognized by Hsps and sHsps. Together with these unfolded or misfolded proteins, Hsps and sHsps form a complex. In addition, Hsps recover unfolded or misfolded proteins back to their native form using ATP. If unfolded or misfolded protein are not recognized by the Hsp/sHsps, these unfolded or misfolded proteins are capable of forming aggregates

Fig. 2

The putative role of chaperones in amyloid-β (Aβ) fibril formation, proteolytic breakdown, and clearance from the brain. In Alzheimer’s disease, soluble Aβ, predominantly produced in neurons, is converted into β-sheet rich protofibrils and eventually forms mature Aβ fibrils. The conversion from soluble Aβ to protofibrils and fibrils, which accumulate in senile plaques and cerebral amyloid angiopathy, is enhanced by chaperones as apolipoprotein E (ApoE), Gelsolin, α₁-antichymotrypsin (ACT) and several heparan sulphate proteoglycans (HSPGs), which function as catalysts. In contrast, the heat shock protein family, tissue-type plasminogen activator (tPA) and complement factors prevent the transition of soluble Aβ into protofibrils and mature fibrils. Furthermore, heat shock proteins and tPA stimulate the proteolytic breakdown of (proto)fibrils, whereas HSPGs prevent this breakdown. Finally, the clearance of Aβ from the brain across the blood–brain barrier is stimulated by ApoE, ApoJ, and α₂-macroglobulin (α2M), whereas complement factors stimulate phagocytosis-mediated clearance of Aβ by activated microglia and astrocytes