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Review
. 2021 Jul 12:13:703876.
doi: 10.3389/fnagi.2021.703876. eCollection 2021.

Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer's Disease

Jose L Martinez  1   2 , Matthew D Zammit  2   3 , Nicole R West  1   2 , Bradley T Christian  2   3   4 , Anita Bhattacharyya  2   5
Affiliations
Review

Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer's Disease

Jose L Martinez et al. Front Aging Neurosci. .

Erratum in

Abstract

Down syndrome (DS, trisomy 21) is characterized by intellectual impairment at birth and Alzheimer's disease (AD) pathology in middle age. As individuals with DS age, their cognitive functions decline as they develop AD pathology. The susceptibility to degeneration of a subset of neurons, known as basal forebrain cholinergic neurons (BFCNs), in DS and AD is a critical link between cognitive impairment and neurodegeneration in both disorders. BFCNs are the primary source of cholinergic innervation to the cerebral cortex and hippocampus, as well as the amygdala. They play a critical role in the processing of information related to cognitive function and are directly engaged in regulating circuits of attention and memory throughout the lifespan. Given the importance of BFCNs in attention and memory, it is not surprising that these neurons contribute to dysfunctional neuronal circuitry in DS and are vulnerable in adults with DS and AD, where their degeneration leads to memory loss and disturbance in language. BFCNs are thus a relevant cell target for therapeutics for both DS and AD but, despite some success, efforts in this area have waned. There are gaps in our knowledge of BFCN vulnerability that preclude our ability to effectively design interventions. Here, we review the role of BFCN function and degeneration in AD and DS and identify under-studied aspects of BFCN biology. The current gaps in BFCN relevant imaging studies, therapeutics, and human models limit our insight into the mechanistic vulnerability of BFCNs in individuals with DS and AD.

Keywords: Alzheimer’s disease; basal forebrain cholinergic neurons; down syndrome; neurodegeneration; pluripotent stem cell.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Postulated mechanisms of BFCN degeneration. Created with BioRender.
FIGURE 2
FIGURE 2
Human stem cell derived BFCNs. Immunofluorescence of BFCNs derived from human iPSCs showing neurons (β-tubulin, red), choline acetyltransferase (ChAT, green), and merged image showing co-expression. Scale bar, 100 um.
See this image and copyright information in PMC

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