Alzheimer's disease pathology is attenuated in a CD 38‐deficient mouse model
Open accessAbstract
Objective: Alzheimer's disease (AD)‐associated dementia is due to tissue damage caused by amyloid β (Aβ) deposition within the brain and by accompanying neuroinflammation. The nicotinamide adenine dinucleotide (NAD) glycohydrolase CD38, which is expressed by neurons, astrocytes, and microglial cells, regulates inflammatory and repair processes in the brain and other tissues by degrading NAD and repressing the activity of other NAD‐consuming enzymes and by producing NAD‐derived metabolites that regulate calcium signaling and migration of inflammatory cells. Given the role of CD38 in neuroinflammation and repair, we examined the effect of CD38 deletion on AD pathology. Methods: We crossed APPswePS1ΔE9 (APP.PS) mice with Cd38−/− mice to generate AD‐prone CD38‐deficient animals (APP.PS.Cd38−/−) and examined AD‐related phenotypes in both groups. Results: APP.PS.Cd38−/− mice exhibited significant reductions in Aβ plaque load and soluble Aβ levels compared to APP.PS mice, and this correlated with improved spatial learning. Although CD38 deficiency resulted in decreased microglia/macrophage (MM) accumulation, the transcription profile of the Cd38−/− and Cd38+/+ MM was similar, suggesting that the decreased Aβ burden in APP.PS.Cd38−/− mice was not due to alterations in MM activation/function. Instead, APP.PS.Cd38−/− neuronal cultures secreted less Aβ and this reduction was mimicked when APP.PS neuronal cultures were treated with inhibitors that blocked CD38 enzyme activity or the signaling pathways controlled by CD38‐derived metabolites. Furthermore, β‐ and γ‐secretase activity was decreased in APP.PS.Cd38−/− mice, which correlated with decreased Aβ production. Interpretation: CD38 regulates AD pathology in the APP.PS model of AD, suggesting that CD38 may be a novel target for AD treatment. Ann Neurol 2015;78:88–103
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Knockdown of CD38 in APPswePS1ΔE9 mice reduced Aβ plaques and soluble Aβ levels and increased spatial learning, possibly through upregulation of brain NAD+ levels.
“Knockdown of CD38 in APPswePS1ΔE9 (APP.PS) mice reduced Aβ plaques and soluble Aβ levels, and increased spatial learning, possibly through upregulation of brain NAD+ levels (Blacher et al., 2015).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Blacher et al., 2015
CD38 expression increases in the course of Alzheimer disease progression.
“CD38 expression increases in the course of Alzheimer disease progression159–161”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [159]
An Alzheimer disease mouse model lacking CD38 has elevated brain NAD+ levels and shows a milder disease phenotype.
“an Alzheimer disease mouse model lacking CD38 (Cd38-knockout mice), which results in elevated NAD+ levels in their brains, shows a milder disease phenotype159.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [159]
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- Authors
- Blacher, E., Dadali, T., Bespalko, A., Haupenthal, V. J., Grimm, M. O. W., Hartmann, T., Lund, F. E., Stein, R., & Levy, A.
- Affiliations
- Tel Aviv University (IL)
- University of Alabama at Birmingham (US)
- Saarland University (DE)
- Corresponding author
- Stein, Reuven
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2015-05-25
- Volume
- 78
- Issue
- 1
- Pages
- 88-103
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC6929692
- OpenAlex
- W1787383112
- Cited by
- 117
- References
- 48
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 21 · 2023: 13 · 2022: 9 · 2021: 17 · 2020: 13 · 2019: 8 · 2018: 4 · 2017: 6 · 2016: 1 · 2015: 1
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Foundation for the National Institutes of Health (NIH AI 063399)
- U.S.-Israel Binational Science Foundation (2011054, 2007061)
- Adams Super-Center for Brain Research at Tel-Aviv University
- DFG
- EU FP7 (211696)
- National Network of Excellence in Neuroscience
- the HOMFORexzellent 2011
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, CD38, NAD glycohydrolase, amyloid-beta, neuroinflammation, microglia/macrophages, beta-secretase, gamma-secretase, spatial learning, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Behavior, Animal, Brain, Cell Movement, Cells, Cultured, Disease Models, Animal, Macrophages, Membrane Glycoproteins, Mice, Transgenic, RNA, Messenger, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Mice, Knockout, Mice, ADP-ribosyl Cyclase 1, Amyloid Precursor Protein Secretases, Plaque, Amyloid, Transcriptome, Spatial Learning
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