Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy

Abstract

Autism and Alzheimer's disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-β precursor protein-α has been shown to be elevated in severe autism, leading to the ‘anabolic hypothesis' of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-values <0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of α-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg2+) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed.

Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder

“…First of all, homocysteine is an endogenous glutamate receptor agonist which acts on N-methyl-d-aspartate (NMDA) and both group I metabotropic receptor subtypes (Shi et al, 2003;Poddar and Paul 2013). Alteration of glutamatergic signalling via the NMDA receptor in the brain of subjects with ASD has also recently been described (Zeidán-Chuliá et al, 2014). The interaction between homocysteine and glutamatergic neurotransmission appears an interesting substrate to explain the effects of this substance in the brain in several neuropsychiatric diseases.…”

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

“…These range from genes for different signaling cascades, to apoptosis pathways and synaptic plasticity (Zeidán-Chuliá et al 2014). Several studies involving gene expression microarray analysis provide evidence of abnormalities in peripheral blood leukocytes in autistic subjects that could provide a biomarker for a genetic and/or environmental predisposition to the disorder (Gregg et al 2008;Alter et al 2011).…”

Genetic effect of interleukin-1 beta (C-511T) polymorphism on the structural covariance network and white matter integrity in Alzheimer’s disease

“…Recent neuroscience studies have supported that cognitive function is highly reflective of the architecture of the neuronal network scaffold [35]. As the potential mechanisms of genetic-based neurobiology are still under investigation [36–39], the exploration of IL-1 beta functional polymorphism may address how genetic variations may affect the organization of the GM and white matter (WM) integrities. The neuroimaging biomarkers of SCN and WMH spatial distribution can be used to test the influence of the genotype groups with regards to inflammatory processes on disease-related degeneration.…”