Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links.
Neurology
; 76(15): 1344-52, 2011 Apr 12.
Article
in En
| MEDLINE
| ID: mdl-21482951
ABSTRACT
The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-ß peptide (Aß), Aß precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted α form of the amyloid-ß precursor protein (sAPPα) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPα levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPα level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPα and production of insoluble Aß would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autistic Disorder
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Amyloid beta-Protein Precursor
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Receptors, Metabotropic Glutamate
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Fragile X Mental Retardation Protein
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Alzheimer Disease
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Fragile X Syndrome
Limits:
Humans
Language:
En
Journal:
Neurology
Year:
2011
Document type:
Article
Affiliation country: