Elsevier

Progress in Neurobiology

Volume 151, April 2017, Pages 101-138
Progress in Neurobiology

Review article
Monoaminergic neuropathology in Alzheimer’s disease

https://doi.org/10.1016/j.pneurobio.2016.04.001Get rights and content

Highlights

  • Monoaminergic systems are altered in Alzheimer’s disease.

  • Noradrenergic LC and serotonergic DRN are among the first affected by tau pathology.

  • Changes in DRN and LC lead to the deterioration of the sleep-wake cycle in AD.

  • Depression in preclinical AD further indicates monoaminergic alteration in AD.

  • In view of its early involvement in AD, the serotonergic system could serve as a therapeutic target.

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.

Section snippets

Clinical and neuropathological criteria for AD diagnosis

Alzheimer’s disease (AD) accounts for 60–70% of cases of dementia (World Health Organization, WHO Fact Sheet No. 362, March 2015). The report of Alzheimer’s Disease International (ADI, The World Alzheimer Report, 2015) showed that nearly 35.6 million people suffered from dementia in 2012. It is estimated that this number will quadruple by 2050. Therefore, the WHO in 2012 declared AD a global public health priority. There is still no effective treatment to prevent or cure AD. Currently, approved

Serotonergic system

The impairment of serotonergic system in AD was shown in humans both in vivo and postmortem. Early non-cognitive behavioral and psychological symptoms of dementia (BPSD), such as disturbances in mood, emotion expression and recognition (Waanders-Oude Elferink et al., 2015), appetite, sleep-wake cycle, confusion, agitation, and depression are probably clinical signs of serotonergic nuclei involvement in AD (Šimić et al., 2009). One of them, sundowning (the increase in one or more abnormal

Alterations of the serotonergic system in AD

Similarly to NIA/AA guidelines, the current clinical criteria for diagnosis of AD of the American Psychiatric Association (DSM-5) are mostly focused on cognitive deficits produced by the dysfunction of hippocampal and association neocortical areas. These changes are neuropsychologically scored as number of points that, in the most commonly used Mini-Mental State Examination (MMSE), ranges from 0 to 30 points, where 30 reflects normal mental status across many cognitive domains (Folstein et al.,

Conclusions

Pathological changes in monoaminergic nuclei, particularly the noradrenergic LC and serotonergic DRN, but also dopaminergic, histaminergic, and melatonergic nuclei and pathways, observed during the early course of AD probably have a profound influence not only on the complex symptoms and pathogenesis in AD, but also in other primary and secondary tauopathies, especially FTD (Boban et al., 2010). The link between depression and AD, depression being a frequent preclinical manifestation of AD, is

Acknowledgments

This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems

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