RETRACTED ARTICLE: p62 improves AD-like pathology by increasing autophagy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-β 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 amyloid-β levels and plaque load. Using complementary genetic and pharmacologic approaches, we found that the p62-mediated changes in Aβ were due to an increase in autophagy. To this end, we showed that removing the LIR domain of p62, which facilitates p62-mediated selective autophagy, or blocking autophagy with a pharmacological inhibitor, was sufficient to prevent the decrease in Aβ. Overall, these data provide the first direct in vivo evidence showing that p62 regulates Aβ turnover.

p62/SQSTM1 – steering the cell through health and disease

“…Expression levels of SQSTM1 are decreased in several neurodegenerative diseases owing to age-related DNA oxidative damage (Du et al, 2009a,b). Accordingly, induction of Sqstm1 through gene therapy has been shown to decrease the levels of amyloid beta precursor protein through an activation of autophagy and to rescue cognitive deficits in mice models of Alzheimer's disease (Caccamo et al, 2017).…”

Autophagy Receptors and Neurodegenerative Diseases

“…In mice, loss of p62 resulted in neuropathological lesions, accumulation of hyperphosphorylated [ 1 9 9 _ T D $ D I F F ] tau, synaptic deficiencies and [ 1 9 7 _ T D $ D I F F ] tau tangle-like structures [92]. In agreement with the neuroprotective function of p62 in AD, p62 was shown to regulate Ab levels through autophagy; overexpression of p62 rescues cognitive deficits in the APP/PS1 mouse model of AD, which was accompanied by a decrease in Ab levels and plaque load [93].…”

Targeting Alzheimer's disease with gene and cell therapies

“…In addition, p62/SQSTM1 strongly binds hyperphosphorylated tau and NFTs , most likely in an attempt to target them for degradation. Indeed, in a gene therapy approach, overexpression of p62/SQSTM1 using AAV bilateral injections into the lateral ventricles rescues cognitive deficits in APP/PS1 mice . The treatment also decreased Aβ levels and plaque formation thus proving the first in vivo evidence of Aβ turnover by p62/SQSTM1.…”