PTEN recruitment controls synaptic and cognitive function in Alzheimer's models.
Nat Neurosci
; 19(3): 443-53, 2016 Mar.
Article
em En
| MEDLINE
| ID: mdl-26780512
ABSTRACT
Dyshomeostasis of amyloid-ß peptide (Aß) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aß appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aß-induced depression. Mechanistically, Aß triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aß-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aß-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aß signaling.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transtornos Cognitivos
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Transmissão Sináptica
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PTEN Fosfo-Hidrolase
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Doença de Alzheimer
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article