ArticleActa neuropathologica2021
ApoE4 inhibition of VMAT2 in the locus coeruleus exacerbates Tau pathology in Alzheimer's disease.
Article in Acta neuropathologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.CNS neuroscience & therapeutics · 2024Pooled it
- ApoE4 as a Therapeutic Target in Epilepsy: From Pathogenic Mechanisms to Precision Medicine.CNS neuroscience & therapeutics · 2026Review
- Sleep complaints and genetic risk of Alzheimer's disease in older women: associations with memory and tau deposition.The journal of prevention of Alzheimer's disease · 2026Article
- A locus coeruleus-centric framework for novelty, salience, and gamma oscillations: implications for neurostimulation, aging, and disease.Frontiers in aging neuroscience · 2026Article
- Soluble CSF1R alleviates microgliopathy in a CSF1R-related leukoencephalopathy (CRL) mouse model.Journal of neuroinflammation · 2025Article
- Impact of Alzheimer's disease risk factors and local neuromelanin content on the transcriptomic landscape of the human locus coeruleus.bioRxiv : the preprint server for biology · 2025Article
- Regenerating Locus Coeruleus-Norepinephrine (LC-NE) Function: A Novel Approach for Neurodegenerative Diseases.Cell proliferation · 2025Review
- ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer's disease.Neuron · 2025Article
- Fading Blue: Exploring the Causes of Locus Coeruleus Damage Across the Lifespan.Antioxidants (Basel, Switzerland) · 2025Review
- Multi-functional role of apolipoprotein E in neurodegenerative diseases.Frontiers in aging neuroscience · 2025Review
- Article
- The Neuroanatomy of Induced Pluripotent Stem Cells: In Vitro Models of Subcortical Nuclei in Neurodegenerative Disorders.Current issues in molecular biology · 2024Review
- Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition.Nature aging · 2024Article
- Behavioral and histological analyses of the mouseFrontiers in neuroscience · 2024Article
- Roles of ApoE4 on the Pathogenesis in Alzheimer's Disease and the Potential Therapeutic Approaches.Cellular and molecular neurobiology · 2023Review
- Riddles in the dark: Decoding the relationship between neuromelanin and neurodegeneration in locus coeruleus neurons.Neuroscience and biobehavioral reviews · 2023Review
- Mitochondrial Dysfunction Links to Impaired Hippocampal Serotonin Release in a Mouse Model of Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2023Article
- APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer's disease pathology and brain diseases.Molecular neurodegeneration · 2022Review
- Losartan Mitigates Oxidative Stress in the Brains of Aged and Inflamed IL-10-/- Mice.The journals of gerontology. Series A, Biological sciences and medical sciences · 2022Article
- Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis.Journal of neurology, neurosurgery, and psychiatry · 2022Article
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7 authors at 2 institutions in 1 country.
Funding
Abstract
ApoE4 enhances Tau neurotoxicity and promotes the early onset of AD. Pretangle Tau in the noradrenergic locus coeruleus (LC) is the earliest detectable AD-like pathology in the human brain. However, a direct relationship between ApoE4 and Tau in the LC has not been identified. Here we show that ApoE4 selectively binds to the vesicular monoamine transporter 2 (VMAT2) and inhibits neurotransmitter uptake. The exclusion of norepinephrine (NE) from synaptic vesicles leads to its oxidation into the toxic metabolite 3,4-dihydroxyphenyl glycolaldehyde (DOPEGAL), which subsequently activates cleavage of Tau at N368 by asparagine endopeptidase (AEP) and triggers LC neurodegeneration. Our data reveal that ApoE4 boosts Tau neurotoxicity via VMAT2 inhibition, reduces hippocampal volume, and induces cognitive dysfunction in an AEP- and Tau N368-dependent manner, while conversely ApoE3 binds Tau and protects it from cleavage. Thus, ApoE4 exacerbates Tau neurotoxicity by increasing VMAT2 vesicle leakage and facilitating AEP-mediated Tau proteolytic cleavage in the LC via DOPEGAL.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.