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Deposition of amyloid plaques in limbic and associative cortices is amongst the most recognized histopathologic hallmarks of Alzheimer's disease. Despite decades of research, there is a lack of consensus over the impact of plaques on neuronal function, with their role in cognitive decline and memory loss undecided. Evidence has emerged suggesting complex and localized axonal pathology around amyloid plaques, with a significant fraction of swellings and dystrophies becoming enriched with putative synaptic vesicles and presynaptic proteins normally colocalized at hotspots of transmitter release. In the absence of hallmark active zone proteins and postsynaptic receptive elements, the axonal swellings surrounding amyloid plaques have been suggested as sites for ectopic release of glutamate, which under reduced clearance can lead to elevated local excitatory drive. Throughout this review, we consider the emerging data suggestive of amyloid plaques as hotspots of compulsive glutamatergic activity. Evidence for local and long-range effects of nonsynaptic glutamate is discussed in the context of circuit dysfunctions and neurodegenerative changes of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Alpha rhythm (8 to 12 Hz) observed in EEG over human posterior cortex is prominent during eyes‐closed (EC) resting and attenuates during eyes‐open (EO) resting. Research shows that the degree of EC‐to‐EO alpha blocking or alpha desynchronization, termed alpha reactivity here, is a neural marker of cognitive health. We tested the role of acetylcholine in EC‐to‐EO alpha reactivity by applying a multimodal neuroimaging approach to a cohort of young adults and a cohort of older adults. In the young cohort, simultaneous EEG‐fMRI was recorded from twenty‐one young adults during both EO and EC resting. In the older cohort, functional MRI was recorded from forty older adults during EO and EC resting, along with FLAIR and diffusion MRI. For a subset of twenty older adults, EEG was recorded during EO and EC resting in a separate session. In both young and older adults, functional connectivity between the basal nucleus of Meynert (BNM), the major source of cortical acetylcholine, and the visual cortex increased from EC to EO, and this connectivity increase was positively associated with alpha reactivity; namely, the stronger the BNM‐visual cortex functional connectivity increase from EC to EO, the larger the EC‐to‐EO alpha desynchronization. In older adults, lesions of the fiber tracts linking BNM and visual cortex quantified by leukoaraiosis volume, associated with reduced alpha reactivity. These findings support a role of acetylcholine and particularly cholinergic pathways in mediating EC‐to‐EO alpha reactivity and suggest that impaired alpha reactivity could serve as a marker of the integrity of the cholinergic system. [ABSTRACT FROM AUTHOR]

Introduction: Numerous studies have characterized impaired cerebral functioning in nicotine-addicted individuals. Whereas nicotine interacts with multiple neurotransmitters in cortical and subcortical circuits, it directly targets the cholinergic system, sourced primarily from the basal nucleus of Meynert (BNM). However, no studies have examined how this cholinergic system is influenced by cigarette smoking. Here, we addressed this gap of research.Methods: Using a dataset from the Functional Connectome Projects, we investigated this issue by contrasting seed-based BNM connectivity of 40 current smokers and 170 age- and gender-matched nonsmokers. We followed our data analytic routines in recent work and examined differences between smokers and nonsmokers in men and women combined as well as separately.Results: Compared to nonsmokers, female but not male smokers demonstrated greater positive BNM connectivity to the supplementary motor area, bilateral anterior insula, and right superior temporal/supramarginal gyri as well as greater negative connectivity to the posterior cingulate cortex and precuneus. Further, BNM connectivity to the supplementary motor area is negatively correlated to the Fagerström Test for Nicotine Dependence score in male but not female smokers.Conclusions: Along with a previous report of upregulated nicotinic acetylcholine receptor in male but not female smokers, these new findings highlight functional changes of the cholinergic systems in cigarette smokers. The results suggest sex-specific differences in cholinergic dysregulation and a need for multiple imaging modalities to capture the neural markers of nicotine addiction.Implications: Nicotine influences cognition via cholinergic projections of the basal forebrain to the cerebral cortex. This study examined changes in resting-state whole-brain functional connectivity of the BNM in cigarette smokers. The new findings elucidate for the first time sex differences in BNM-cerebral connectivity in cigarette smoking. [ABSTRACT FROM AUTHOR]

Functional overviews of cholinergic mechanisms in the cerebral cortex have traditionally focused on the release of acetylcholine with modulator and transmitter effects. Recently, however, data have emerged that extend the role of acetylcholine and cholinergic innervations to a range of housekeeping and metabolic functions. These include regulation of amyloid precursor protein (APP) processing with production of amyloid β (Aβ) and other APP fragments and control of the phosphorylation of microtubule-associated protein (MAP) tau. Evidence has been also presented for receptor-ligand like interactions of cholinergic receptors with soluble Aβ peptide and MAP tau, with modulator and signaling effects. Moreover, high-affinity binding of Aβ to the neurotrophin receptor p75 (p75NTR) enriched in basalo-cortical cholinergic projections has been implicated in clearance of Aβ and nucleation of amyloid plaques. Here, we critically evaluate these unorthodox cholinergic mechanisms and discuss their role in neuronal physiology and the biology of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]