Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer’s Disease

2021 ◽  
Author(s):  
Melissa J. Alldred ◽  
Sai C. Penikalapati ◽  
Sang Han Lee ◽  
Adriana Heguy ◽  
Panos Roussos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Basal Forebrain ◽  
Molecular Basis ◽  
Cholinergic Neurons ◽  
Basal Forebrain Cholinergic Neurons

scholarly journals Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Jose L. Martinez ◽  
Matthew D. Zammit ◽  
Nicole R. West ◽  
Bradley T. Christian ◽  
Anita Bhattacharyya
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Basal Forebrain ◽  
Critical Role ◽  
Memory Loss ◽  
Cholinergic Neurons ◽  
Cholinergic Innervation ◽  
Attention And Memory ◽  
Basal Forebrain Cholinergic Neurons

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.

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

2021 ◽  
Vol 13 ◽  
Author(s):  
Jose L. Martinez ◽  
Matthew D. Zammit ◽  
Nicole R. West ◽  
Bradley T. Christian ◽  
Anita Bhattacharyya
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Basal Forebrain Cholinergic Neurons

Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer’s Disease

2020 ◽  
Author(s):  
Melissa J. Alldred ◽  
Sai C. Penikalapati ◽  
Sang Han Lee ◽  
Adriana Heguy ◽  
Panos Roussos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Basal Forebrain ◽  
Differentially Expressed Gene ◽  
Cholinergic Neurons ◽  
Bioinformatic Analysis ◽  
Selective Vulnerability ◽  
Neuronal Population ◽  
Single Population

Abstract Background: Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer’s disease (AD). Current therapeutics have been unsuccessful in slowing disease progression, likely due to complex pathological interactions and dysregulated pathways that are poorly understood. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration. Methods: We utilized Ts65Dn mice to understand mechanisms underlying BFCN degeneration to identify novel targets for therapeutic intervention. We performed high-throughput, single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCNs, using laser capture microdissection to individually isolate ~500 choline acetyltransferase-immunopositive neurons in Ts65Dn and normal disomic (2N) mice at 6 months of age (MO). Results: Ts65Dn mice had unique MSN BFCNs transcriptomic profiles at ~6 MO clearly differentiating them from 2N mice. Leveraging Ingenuity Pathway Analysis and KEGG analysis, we linked differentially expressed gene (DEG) changes within MSN BFCNs to several canonical pathways and aberrant physiological functions. The dysregulated transcriptomic profile of trisomic BFCNs provides key information underscoring selective vulnerability within the septohippocampal circuit. Conclusions: We propose both expected and novel therapeutic targets for DS and AD, including specific DEGs within cholinergic, glutamate, GABAergic, and neurotrophin pathways, as well as select targets for repairing oxidative phosphorylation status in neurons. We demonstrate and validate an interrogative quantitative bioinformatic analysis of a key dysregulated neuronal population linking single population transcript changes to an established pathological hallmark associated with cognitive decline for therapeutic development in human DS and AD.

scholarly journals The Promoted Generation of Basal Forebrain Cholinergic Neurons from Neural Progenitor Cells on Three-dimensional Graphene foam Scaffold

2021 ◽  
Author(s):  
Ziyun Jiang ◽  
Lingyan Yang ◽  
Linhong Zhou ◽  
Miao Xiao ◽  
Sancheng Ma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Progenitor Cells ◽  
Basal Forebrain ◽  
Neural Progenitor Cells ◽  
Three Dimensional ◽  
Cholinergic Neurons ◽  
Neural Progenitor ◽  
Graphene Foam ◽  
Basal Forebrain Cholinergic Neurons

Abstract Background: An early substantial loss of basal forebrain cholinergic neurons (BFCNs) is a common property of Alzheimer’s disease and the generation of functional BFCNs is related to learning and memory deficits. As a biocompatible and conductive scaffold for growth of neural stem cells, three-dimensional graphene foam (3D-GF) supports applications in tissue engineering and regenerative medicine. Although its effects on differentiation have been demonstrated, the effect of 3D-GF scaffold on the generation of BFCNs still remains unknown. Methods: In this study, we used 3D-GF as a culture substrate for neural progenitor cells (NPCs) and demonstrated that this scaffold material promotes the differentiation of BFCNs while maintaining excellent cell viability and proliferation. Results: Immunofluorescence analysis, RT-PCR, western blotting and ELISA revealed that the efficiency of BFCN differentiation on 3D-GF was significantly greater than that on tissue culture polystyrene substrates. Furthermore, a cell adhesion study suggested that 3D-GF scaffold enhances the expression of adhesion proteins including vinculin, integrin and N-cadherin. These findings indicate that 3D-GF scaffold materials are excellent candidates for the differentiation of BFCNs from NPCs. Conclusion: These results suggest new opportunities for the application of 3D-GF scaffold as a neural scaffold for Alzheimer’s disease therapies based on NPCs. Trial registration: Not applicable.

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