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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-β peptide (Aβ), Aβ 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-β 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 Aβ 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.
Footnotes
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Study funding: Supported by the Zenith Award from the Alzheimer's Association and the NIH (AG18379 and AG18884) to D.K.L.
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- Aβ
- amyloid-β
- AD
- Alzheimer disease
- APP
- Aβ precursor protein
- FMRP
- fragile X mental retardation protein
- FXS
- fragile X syndrome
- FXTAS
- fragile X–associated tremor/ataxia syndrome
- LEARn
- latent early-life associated regulation
- LTD
- long-term depression
- LTP
- long-term potentiation
- mGluR5
- metabotropic glutamate receptor 5
- sAPPα
- secreted α form of the amyloid-β precursor protein
- UTR
- untranslated region
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Supplemental data at www.neurology.org
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References e1–e45 are available on the Neurology® Web site at www.neurology.org.
- Received April 14, 2010.
- Accepted December 22, 2010.
- Copyright © 2011 by AAN Enterprises, Inc.
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