All neurodegenerative diseases are characterized by the build-up of proteins within or around nerve cells. In all these conditions, the proteins adopt an abnormal three-dimensional conformation, causing them to become insoluble and prone to aggregation. In Alzheimer’s Disease, amyloid-beta protein accumulates to form extracellular deposits called senile plaques, and the hyperphosphorylated form of a microtubule-associated protein called tau (herafter referred to as p-tau) accumulates within neurons to form structures called neurofibrillary tangles (NFTs).
NFTs were first described by Alois Alzheimer, after his post-mortem examination of the brain of Auguste Deter, the index case of the disease which bears his name. They are found in the pyramidal cells of the neocortex, particularly in temporal lobe structures such as the hippocampus and amygdala, where they appear as flame-shaped structures which fill the cell body and extend into the apical dendrite (left). Tau is normally unfolded and soluble; in Alzheimer’s, and related conditions, hyperphosphorylation causes the formation of a tight hairpin loop in the protein, which makes it insoluble. Electron microscopy reveals that, within cortical neurons, NFTs consist of tau fibrils with a diameter of 10 nanometres, coiled around each other to form paired helical structures.
The role of amyloid plaques and NFTs in Alzheimer’s disease pathogenesis is not well understood, although the latter are more closely correlated than the former with neuronal dysfunction and the severity of dementia. Recently, researchers have obtained evidence that this protein aggregation may be due to impaired protein degradation, leading to a failure to remove abnormally folded proteins. Also implicated in this process are molecular chaperones, which are involved in recognizing proteins with an abnormal configuration and refolding them; earlier this year, for example, heat shock protein (HSP) 90, a chaperone involved in protein folding and degradation, was implicated in prion diseases.
Leonard Petrucelli and his colleagues at the Mayo Clinic College of Medicine provide more evidence of the role of molecular chaperones in neurodegenerative processes. The findings, which show that inhibition of HSP90 by a small molecule called EC102 leads to increased degradation of toxic p-tau aggregations, are published in advance on the website of the Journal of Clinical Investigation.
Previous work by Petrucelli’s team showed that small molecule inhibitors dramatically increase the degradation of p-tau. It was also known that p-tau aggregation increases with loss of function of the carboxy terminus of HSP70-interacting protein (CHIP). To determine the role of the CHIP protein in protein degradation, the researchers performed experiments on cultured HeLa cells overexpressing human tau protein. Using small inhibitory RNAs (siRNAs), expression of the CHIP gene was blocked; as a result, tau protein accumulated in the cells. Conversely, antibody staining showed that, when HSP90 expression was blocked, the number of CHIP-tau complexes increased.
A strain of transgenic mice overexpressing the mutated form of human tau protein was then created. Intraperitoneal injection of EC102 led to increased degradation of the abnormal protein, and reduction in p-tau aggregates by approximately 50%. Finally, the brains of deceased Alzheimer’s patients were compared with the brains of controls who had died of other causes. HSP90 was found to be tightly bound to p-tau aggregates in the affected regions of the Alzheimer’s patients, but not in the controls.
Taken together, the data suggest that CHIP mediates the interactions of molecular chaperones with their “client” proteins, such as p-tau. It appears that the chaperones compete in binding with abnormal tau protein, and that binding of HSP90 to p-tau aggregates prevents CHIP from recruiting other chaperones that would induce degradation of the aggregates. Inhibition of HSP90 reduces this competition, leading to targeted degradation of p-tau.
The findings also support the idea that there is an age-related loss of molecular chaperone function, which may be exaserbated in Alzheimer’s. Because EC102 can pass through the blood-brain barrier, it, and related compounds, may prove to be effective treatments for Alzheimer’s and other “tauopathies” (conditions in which there is aggregation and deposition of tau protein), such as Pick’s disease, Parkinson’s-associated frontotemporal dementia; supranuclear palsy and corticobasal degeneration;
Dickey, C. A. (2007). The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J. Clin. Invest. DOI: 10.1172/JCI129715. [Full text]