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P62 improves AD-like pathology by increasing autophagy.


ABSTRACT: The multifunctional protein p62 is associated with neuropathological inclusions in several neurodegenerative disorders, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and Alzheimer's disease (AD). Strong evidence shows that in AD, p62 immunoreactivity is associated with neurofibrillary tangles and is involved in tau degradation. However, it remains to be determined whether p62 also plays a role in regulating amyloid-? (A?) aggregation and degradation. Using a gene therapy approach, here we show that increasing brain p62 expression rescues cognitive deficits in APP/PS1 mice, a widely used animal model of AD. The cognitive improvement was associated with a decrease in A? levels and plaque load. Using complementary genetic and pharmacologic approaches, we found that the p62-mediated changes in A? were due to an increase in autophagy. To this end, we showed that removing the LC3-interacting region of p62, which facilitates p62-mediated selective autophagy, or blocking autophagy with a pharmacological inhibitor, was sufficient to prevent the decrease in A?. Overall, we believe these data provide the first direct in vivo evidence showing that p62 regulates A? turnover.

SUBMITTER: Caccamo A 

PROVIDER: S-EPMC5479312 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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p62 improves AD-like pathology by increasing autophagy.

Caccamo A A   Ferreira E E   Branca C C   Oddo S S  

Molecular psychiatry 20160830 6


The multifunctional protein p62 is associated with neuropathological inclusions in several neurodegenerative disorders, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and Alzheimer's disease (AD). Strong evidence shows that in AD, p62 immunoreactivity is associated with neurofibrillary tangles and is involved in tau degradation. However, it remains to be determined whether p62 also plays a role in regulating amyloid-β (Aβ) aggregation and degradation. Using a gene the  ...[more]

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