Ascending monoaminergic systems alterations in Alzheimer's disease. translating basic science into clinical care

Abstract

Extensive neuropathological studies have established a compelling link between abnormalities in structure and function of subcortical monoaminergic (MA-ergic) systems and the pathophysiology of Alzheimer's disease (AD). The main cell populations of these systems including the locus coeruleus, the raphe nuclei, and the tuberomamillary nucleus undergo significant degeneration in AD, thereby depriving the hippocampal and cortical neurons from their critical modulatory influence. These studies have been complemented by genome wide association studies linking polymorphisms in key genes involved in the MA-ergic systems and particular behavioral abnormalities in AD. Importantly, several recent studies have shown that improvement of the MA-ergic systems can both restore cognitive function and reduce AD-related pathology in animal models of neurodegeneration. This review aims to explore the link between abnormalities in the MA-ergic systems and AD symptomatology as well as the therapeutic strategies targeting these systems. Furthermore, we will examine possible mechanisms behind basic vulnerability of MA-ergic neurons in AD.

Keywords: 3,4-Dihydroxyphenylacetic acid; 3-Methoxy-4-hydroxyphenylglycol; 5-HT; 5-HT transporter; 5-HT transporter gene-linked polymorphic region; 5-HTT; 5-HTTLPR; 5-Hydroxyindoleacetic acid; 5-Hydroxytryptamine; 5HIAA; AADC; ACC; AD; APP; AR; ATMX; Adrenergic receptor; Alzheimer's disease; Amnestic mild cognitive impairment; Amyloid precursor protein; Anterior cingulate cortex; Aβ; BDNF; BPSD; Behavioral/psychological symptoms in dementia; Brain-derived neurotrophic factor; CA; COMT; Cathechol-O-methyltranferase; Cognition.; Cornus ammonis; DA; DA transporter; DA β-hydroxylase; DA-ergic; DAT; DBH; DG; DLPFC; DOPAC; DRN; DS; Dentate gyrus; Dopamine; Dopaminergic; Dorsal raphe nucleus; Dorsolateral prefrontal cortex; Down syndrome; EC; Entorhinal cortex; G protein coupled receptor; GPCR; GWAS; Genome-wide association studies; HA; HDC; HMT; HVA; Histamine; Histamine-N-methyl-transferase; Histidine decarboxylase; Homovanillic acid; IDE; IDO; Indoleamine 2,3-dioxygenase; Insulin-degrading enzyme; L-3,4-dihydroxyphenylalanine; L-DOPA; L-DOPS; L-amino acid decarboxylase; L-threo-dihydroxyphenylserine; LC; Locus coeruleus; MA; MA-ergic; MAO; MAO-B; MHPG; MMSE; MRN; MS; Medial septum; Median raphe nucleus; Mini-Mental State Exam; Mitochondrial DNA; Monoamine; Monoamine oxidase; Monoamine oxidase B; Monoaminergic; NAD; NADP; NBM; NFT; NGF; Nerve growth factor; Neurofibrillary tangle; Nicotinamide adenine dinucleotide; Nicotinamide adenine dinucleotide phosphate; Norepinephrine; OFC; Orbitofrontal cortex; PD; PFC; PLC; PP; Parkinson's disease; Perforant path; Phospholipase C; Prefrontal cortex; SAMP8; SNP; SNpc; SSRI; Selective serotonin reuptake inhibitor; Senescence-accelerated prone mouse; Serotonin; Single nucleotide polymorphism; Substantia nigra pars compacta; TH; TMN; TPH; Tele-methylimidazole acetic acid; Tryptophan hydroxylase; Tuberomamillary nucleus; Tyrosine hydroxylase; VMA; VTA; Vanillylmandelic acid; Ventral tegmental area; aMCI; amyloid β; atomoxetine; mtDNA; nucleus basalis magnocellularis; t-MeHA.