Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links

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.

Figure 1. Amyloid-β (Aβ) precursor protein (APP), fragile X mental retardation protein (FMRP), metabotropic glutamate receptor 5 (mGluR) interaction cycle

Interaction cycle of APP, FMRP, and mGluR in balance. APP mRNA translation is inhibited by FMRP binding to G quartets in the APP coding region. This binding is reversed by mGluR5 activation. Activity of mGluR5 also stimulates secretion of secreted α form of the amyloid-β precursor protein (sAPP) in neuron. In addition, FMRP stimulates neural pruning and synaptic plasticity through other intermediaries.^e45 In a healthy system, FMRP activity and mGluR5 activity work in homeostasis and neural proliferation is balanced, leading to a neurotypical condition.

Figure 2. Fragile X mental retardation protein (FMRP) deficiency results in CNS overgrowth/deficiencies

FMRP deficiency resulting in CNS overgrowth and developmental disorder. When FMRP is eliminated or diminished, translation of amyloid-β (Aβ) precursor protein (APP) mRNA is disinhibited resulting in elevated basal levels of APP protein and the elimination of activity-dependent dynamic APP production. Elevated neural proliferation is not balanced by increased neural pruning, in part due to FMRP deficiency. This could result in CNS neural overgrowth and leads to the symptoms of fragile X syndrome (FXS) or autism. mGluR5 = metabotropic glutamate receptor 5; sAPPα = secreted α form of the amyloid-β precursor protein. Bold arrows indicate predominant pathways.

Figure 3. Overcoming fragile X mental retardation protein (FMRP) deficiency

Use of metabotropic glutamate receptor 5 (mGluR5) inhibitors to ameliorate FMRP deficiency. mGluR5 activity in amyloid-β (Aβ) precursor protein (APP) mRNA translation is disinhibitory, so blocking mGluR5 is not likely to alter APP translation levels. Secretion of secreted α form of the amyloid-β precursor protein (sAPP) may, nevertheless, be reduced by reducing mGluR5 stimulation of sAPP secretion in neurons. Reduced sAPP secretion provides lower levels of available product of the α-secretase pathway, reducing symptoms of fragile X syndrome (FXS) or autism. Bold arrows indicate predominant pathways.