Monoaminergic neuropathology in Alzheimer’s disease

Abstract

None of the proposed mechanisms of Alzheimer’s disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5–20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD.

A clinicopathological approach to the diagnosis of dementia

“…From an anatomical standpoint, the abnormal intracellular aggregation of tau may begin subcortically in noradrenergic projection neurons of the locus coeruleus 36–39 , extending along functional networks subserving the limbic system. Noradrenergic deficiency, and ensuing symptoms such as attentional deficits, are intimately connected to the neuroanatomical substrates of AD.…”

Sex Hormones and Alzheimer’s Disease

“…The neurochemical changes in AD include extensive serotonergic denervation in the hippocampus and neocortex, depletion of the cholinergic neurons in the basal forebrain, loss of >70% of noradrenergic locus coeruleus neurons, reduction of dopamine, dopamine metabolites and dopamine receptors, histaminergic tuberomammillary nucleus degeneration and impaired melatonin secretion and action in the pineal body and suprachiasmatic hypothalamic nucleus, respectively [23].…”

“…Common affected genes include APP (genes encoding γ-secretase complex), presenelin-1 (PSNL1) and presenelin-2 (PSNL2) gene mutation in chromosomes 21, 14 and 1, respectively. Overexpression of these genes results in increased production of the highly hydrophobic fibrillogenic longer Aβ-42 and on the expense of the relatively shorter Aβ-40 [23].…”

Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases

“…As neuronal degeneration in AD also affects monoaminergic systems (Trillo et al, 2013), dopaminergic and serotonergic dysfunction has been also proposed to be involved (Martorana and Koch, 2014; Claeysen et al, 2015; Šimić et al, 2016), suggesting additional therapeutic targets for AD. Newly synthetized molecules with neuroprotective and multimodal mechanisms of action, currently in different phases of preclinical or clinical investigations (Dias and Viegas, 2014), act not only as AChEI and modulators of Aβ-aggregation (Tonelli et al, 2015), but also at voltage-dependent calcium channels (León and Marco-Contelles, 2011), MAO activity (Bautista-Aguilera et al, 2014), 5-HT 3 receptors (Fakhfouri et al, 2012) and N-methyl-D-aspartate (NMDA) receptors (Simoni et al, 2012).…”