Abstract
Impairment of neuronal proteostasis is a hallmark of Alzheimer’s and other neurodegenerative diseases. However, the underlying molecular mechanisms leading to pathogenic protein aggregation, and the role of secretory chaperone proteins in this process, are poorly understood. We have previously shown that the neural-and endocrine-specific secretory chaperone 7B2 potently blocks in vitro fibrillation of Aβ42. To determine whether 7B2 can function as a chaperone in vivo, we measured plaque formation and performed behavioral assays in 7B2-deficient mice in an hAPPswe/PS1dE9 Alzheimer’s model mouse background. Surprisingly, immunocytochemical analysis of cortical levels of thioflavin S- and Aβ-reactive plaques showed that APP mice with a partial or complete lack of 7B2 expression exhibited a significantly lower number and burden of thioflavin S-reactive, as well as Aβ-immunoreactive, plaques. However, 7B2 knockout did not affect total brain levels of either soluble or insoluble Aβ. While hAPP model mice performed poorly in the Morris water maze, their brain 7B2 levels did not impact performance. Since 7B2 loss reduced amyloid plaque burden, we conclude that brain 7B2 can impact Aβ disposition in a manner that facilitates plaque formation. These results are reminiscent of prior findings in hAPP model mice lacking the ubiquitous secretory chaperone clusterin.
Highlights
Protein chaperones play an important role in maintaining neuronal proteostasis and in preventing aberrant protein aggregation within the brain
The total platform crosses indicated a trend towards decreased performance in all APP transgene-positive mice, with hAPPtg7B2+/− and hAPPtg7B2−/− showing a significant decrease
A variety of chaperone proteins contribute to neuroprotection in cellular and animal models of neurodegeneration
Summary
Protein chaperones play an important role in maintaining neuronal proteostasis and in preventing aberrant protein aggregation within the brain. Perhaps due to its high metabolic activity, the brain appears to be susceptible to proteostatic insult and expresses a variety of chaperone proteins to assist with proper protein handling. Derangement of this process in neurodegenerative disease leads to protein deposition in the form of Lewy bodies (Parkinson’s disease) or amyloid plaques/tau tangles (Alzheimer’s disease and other dementias). While many secreted chaperones are clearly active as anti-aggregants in vitro (reviewed in9), it has been difficult to parse out their actual biological roles during neurodegenerative disease processes. In the experiments described below, we used 7B2 knockout mice to investigate the effect of 7B2 deficiency on plaque formation and cognition in an Alzheimer’s model mouse
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