p62 improves AD-like pathology by increasing autophagy

Antonella Caccamo, E. Ferreira, C. Branca, Salvatore Oddo

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 (Aβ) 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 Aβ 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 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 Aβ. Overall, we believe these data provide the first direct in vivo evidence showing that p62 regulates Aβ turnover.Molecular Psychiatry advance online publication, 30 August 2016; doi:10.1038/mp.2016.139.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Aug 30 2016

Fingerprint

Autophagy
Alzheimer Disease
Pathology
Frontotemporal Lobar Degeneration
Neurofibrillary Tangles
Amyotrophic Lateral Sclerosis
Amyloid
Neurodegenerative Diseases
Genetic Therapy
Psychiatry
Publications
Animal Models
Pharmacology
Brain
Proteins

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

p62 improves AD-like pathology by increasing autophagy. / Caccamo, Antonella; Ferreira, E.; Branca, C.; Oddo, Salvatore.

In: Molecular Psychiatry, 30.08.2016.

Research output: Contribution to journalArticle

Caccamo, Antonella ; Ferreira, E. ; Branca, C. ; Oddo, Salvatore. / p62 improves AD-like pathology by increasing autophagy. In: Molecular Psychiatry. 2016.
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