Genetics of Aggression in Alzheimer’s Disease (AD)

Abstract

Alzheimer’s disease (AD) is a terminal, age-related neurological syndrome exhibiting progressive cognitive and memory decline, however AD patients in addition exhibit ancillary neuropsychiatric symptoms (NPSs) and these include aggression. In this communication we provide recent evidence for the mis-regulation of a small family of genes expressed in the human hippocampus that appear to be significantly involved in expression patterns common to both AD and aggression. DNA array- and mRNA transcriptome-based gene expression analysis and candidate gene association and/or genome-wide association studies (CGAS, GWAS) of aggressive attributes in humans have revealed a surprisingly small subset of six brain genes that are also strongly associated with altered gene expression patterns in AD. These genes encoded on five different chromosomes (chr) include the androgen receptor (AR; chrXq12), brain-derived neurotrophic factor (BDNF; chr11p14.1), catechol-O-methyl transferase (COMT; chr22q11.21), neuronal specific nitric oxide synthase (NOS1; chr12q24.22), dopamine beta-hydroxylase (DBH chr9q34.2) and tryptophan hydroxylase (TPH1, chr11p15.1 and TPH2, chr12q21.1). Interestingly, (i) the expression of three of these six genes (COMT, DBH, NOS1) are highly variable; (ii) three of these six genes (COMT, DBH, TPH1) are involved in DA or serotonin metabolism, biosynthesis and/or neurotransmission; and (iii) five of these six genes (AR, BDNF, COMT, DBH, NOS1) have been implicated in the development, onset and/or propagation of schizophrenia. The magnitude of the expression of genes implicated in aggressive behavior appears to be more pronounced in the later stages of AD when compared to MCI. These recent genetic data further indicate that the extent of cognitive impairment may have some bearing on the degree of aggression which accompanies the AD phenotype.

Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer’s Disease

“…Capn1 activation is also linked to type II diabetes mellitus, and pathways linked to diabetes and metabolic syndrome are dysregulated in Ts BFCNs (108). Nos1, upregulated in Ts BFCNs, also shows increased expression in AD (112,113) and GWAS studies implicate aberrant Nos1 expression in AD (114). Reduction in Gapdh activity has also been shown in AD brain due to oxidative modi cation (115).…”

Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus

“…A major fraction of all secreted extracellular RNAs are sncRNAs in the size range of 15–40 nucleotides derived from specific intracellular bacterial RNAs. These sncRNAs have been speculated to be involved in immune-evasion, intra-species communication, in inter-kingdom genetic exchanges, pathogenicity and/or microbiome-host signaling; indeed protein-, lipid-, and nucleic acid-containing OMVs released by GI tract Gram-negative bacteria can be intensely pro-inflammatory, pathogenic or even lethal to the host (Zhao and Lukiw, 2015 ; Ghosal, 2017 ; Lukiw and Rogaev, 2017 ; unpublished observations). Several important questions remain to be answered: (i) do secreted sncRNAs play any role in microbiome survival, immune evasion and/or antibiotic resistance?…”

Identification of exon skipping events associated with Alzheimer’s disease in the human hippocampus

“…AD). Both increased and decreased expression of NOS1 have been associated with a cognitive disruption in relation to the AD [52]. Therefore, it will be interesting to characterize how the expression of different isoforms and exons contributes to the spectrum of phenotypes related to AD in future work.…”