ArticleAlzheimer's research & therapy2009
Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer's and other neurodegenerative diseases.
Article in Alzheimer's research & therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 95 citations in OpenAlex.
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- Maximum lifespan and brain size in mammals are associated with gene family size expansion related to immune system functions.Scientific reports · 2025Article
- Autoantibody profiles in Alzheimer´s, Parkinson´s, and dementia with Lewy bodies: altered IgG affinity and IgG/IgM/IgA responses to alpha-synuclein, amyloid-beta, and tau in disease-specific pathological patterns.Journal of neuroinflammation · 2024Article
- Gut Microbiota and Immune System Dynamics in Parkinson's and Alzheimer's Diseases.International journal of molecular sciences · 2024Review
- Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Review
- Exploring the Role of Hsp60 in Alzheimer's Disease and Type 2 Diabetes: Suggestion for Common Drug Targeting.International journal of molecular sciences · 2023Review
- Potential of Therapeutic Small Molecules in Apoptosis Regulation in the Treatment of Neurodegenerative Diseases: An Updated Review.Molecules (Basel, Switzerland) · 2022Review
- Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?International journal of molecular sciences · 2022Review
- Protective Role of Capsaicin in Neurological Disorders: An Overview.Neurochemical research · 2022Review
- A Prospective Viewpoint on Neurological Diseases and Their Biomarkers.Molecules (Basel, Switzerland) · 2022Review
- Innate immunity stimulation via CpG oligodeoxynucleotides ameliorates Alzheimer's disease pathology in aged squirrel monkeys.Brain : a journal of neurology · 2021Article
- Autopsy-diagnosed neurodegenerative dementia cases support the use of cerebrospinal fluid protein biomarkers in the diagnostic work-up.Scientific reports · 2021Article
- The Cellular Senescence Stress Response in Post-Mitotic Brain Cells: Cell Survival at the Expense of Tissue Degeneration.Life (Basel, Switzerland) · 2021Review
- Cell of all trades: oligodendrocyte precursor cells in synaptic, vascular, and immune function.Genes & development · 2021Review
- TDP-43 proteinopathy impairs mRNP granule mediated postsynaptic translation and mRNA metabolism.Theranostics · 2021Article
- Clinicopathological Staging of Dynamics of Neurodegeneration and Neuronal Loss in Alzheimer Disease.Journal of neuropathology and experimental neurology · 2021Article
- Neurodegenerative diseases as proteinopathies-driven immune disorders.Neural regeneration research · 2020Review
- Review
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAlzheimer's disease (AD) and a host of other neurodegenerative central nervous system (CNS) proteinopathies are characterized by the accumulation of misfolded protein aggregates. Simplistically, these aggregates can be divided into smaller, soluble, oligomeric and larger, less-soluble or insoluble, fibrillar forms. Perhaps the major ongoing debate in the neurodegenerative disease field is whether the smaller oligomeric or larger fibrillar aggregates are the primary neurotoxin. Herein, we propose an integrative hypothesis that provides new insights into how a variety of misfolded protein aggregates can result in neurodegeneration.
resultsWe introduce the concept that a wide range of highly stable misfolded protein aggregates in AD and other neurodegenerative proteinopathies are recognized as non-self and chronically activate the innate immune system. This pro-inflammatory state leads to physiological senescence of CNS cells. Once CNS cells undergo physiological senescence, they secrete a variety of pro-inflammatory molecules. Thus, the senescence of cells, which was initially triggered by inflammatory stimuli, becomes a self-reinforcing stimulus for further inflammation and senescence. Ultimately, senescent CNS cells become functionally impaired and eventually die, and this neurodegeneration leads to brain organ failure.
conclusionThis integrative hypothesis, which we will refer to as the proteinopathy-induced senescent cell hypothesis of AD and other neurodegenerative diseases, links CNS proteinopathies to inflammation, physiological senescence, cellular dysfunction, and ultimately neurodegeneration. Future studies characterizing the senescent phenotype of CNS cells in AD and other neurodegenerative diseases will test the validity of this hypothesis. The implications of CNS senescence as a contributing factor to the neurodegenerative cascade and its implications for therapy are discussed.
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Registered trials
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.