Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
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.

PubMed Disclaimer

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

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alzheimer’s Association (2021). 2021 Alzheimer’s disease facts and figures. Alzheimers Dement. 17 327–406. 10.1002/alz.12328 - DOI - PubMed
    1. Akeson E. C., Lambert J. P., Narayanswami S., Gardiner K., Bechtel L. J., Davisson M. T. (2001). Ts65Dn – localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome. Cytogenet. Cell Genet. 93 270–276. 10.1159/000056997 - DOI - PubMed
    1. Alldred M. J., Chao H. M., Lee S. H., Beilin J., Powers B. E., Petkova E., et al. (2018). CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer’s disease following maternal choline supplementation. Hippocampus 28 251–268. 10.1002/hipo.22832 - DOI - PMC - PubMed
    1. Alldred M. J., Chao H. M., Lee S. H., Beilin J., Powers B. E., Petkova E., et al. (2019). Long-term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer’s disease. FASEB J. 33 9871–9884. 10.1096/fj.201802669rr - DOI - PMC - PubMed
    1. Alonso A. D., Cohen L. S., Corbo C., Morozova V., ElIdrissi A., Phillips G., et al. (2018). Hyperphosphorylation of Tau associates with changes in its function beyond microtubule stability. Front. Cell. Neurosci. 12:338. 10.3389/fncel.2018.00338 - DOI - PMC - PubMed