Relationship between multifunctional protein “clusterin” and Alzheimer disease

In the Alzheimer disease (AD) brain, senile plaques contain several proteins and cytokines, such as β-amyloid protein (Aβ), interleukin 1, transforming growth factor β1 (TGF β1), and apolipoprotein E, which may contribute to the process of neurodegeneration. Clusterin is also known to colocalize with Aβ deposits in neuritic plaques. Clusterin is a multifunctional protein that causes cell aggregation, binds to β-endorphin, and inhibits the terminal complex formation of complement. Clusterin mRNA and protein are increased in the brains of AD patients. Cytokines such as TGF β1 and interleukin 1 enhance the expression of clusterin, which may link clusterin to inflammatory mechanisms in AD. Aβ, a 39–43 amino acid peptide, is a major component of the senile plaques that are characteristic of AD. Highly aggregated Aβ is implicated in neurodegeneration, e.g., Aβ aggregates spontaneously into fibrillar forms resembling those in plaques that, in experimental models, cause neurotoxicity through oxidative stress. Clusterin inhibits the aggregation of Aβ, which might be neuroprotective according to the aggregation-toxicity hypothesis of Aβ. However, clusterin enhanced the oxidative stress of Aβ. This may extend its neurotoxicity to locations distal from plaques wherever Aβ is present.