Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer's and other neurodegenerative diseases
- PMID: 19822029
- PMCID: PMC2874257
- DOI: 10.1186/alzrt5
Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer's and other neurodegenerative diseases
Abstract
Background: Alzheimer'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.
Results: We 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.
Conclusion: This 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.
Figures

Similar articles
-
Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis.Front Cell Neurosci. 2020 May 19;14:129. doi: 10.3389/fncel.2020.00129. eCollection 2020. Front Cell Neurosci. 2020. PMID: 32508595 Free PMC article. Review.
-
Astrocyte Senescence and Alzheimer's Disease: A Review.Front Aging Neurosci. 2020 Jun 9;12:148. doi: 10.3389/fnagi.2020.00148. eCollection 2020. Front Aging Neurosci. 2020. PMID: 32581763 Free PMC article. Review.
-
Aging Microglia-Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases.Front Aging Neurosci. 2017 Jun 14;9:194. doi: 10.3389/fnagi.2017.00194. eCollection 2017. Front Aging Neurosci. 2017. PMID: 28659790 Free PMC article. Review.
-
Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?Eur Neuropsychopharmacol. 2015 May;25(5):713-24. doi: 10.1016/j.euroneuro.2013.03.007. Epub 2013 May 1. Eur Neuropsychopharmacol. 2015. PMID: 23642796 Review.
-
Neurodegenerative diseases as proteinopathies-driven immune disorders.Neural Regen Res. 2020 May;15(5):850-856. doi: 10.4103/1673-5374.268971. Neural Regen Res. 2020. PMID: 31719246 Free PMC article. Review.
Cited by
-
Clinicopathological Staging of Dynamics of Neurodegeneration and Neuronal Loss in Alzheimer Disease.J Neuropathol Exp Neurol. 2021 Jan 1;80(1):21-44. doi: 10.1093/jnen/nlaa140. J Neuropathol Exp Neurol. 2021. PMID: 33270870 Free PMC article.
-
Comparative analysis of autophagy and tauopathy related markers in cerebral ischemia and Alzheimer's disease animal models.Front Aging Neurosci. 2015 May 19;7:84. doi: 10.3389/fnagi.2015.00084. eCollection 2015. Front Aging Neurosci. 2015. PMID: 26042033 Free PMC article.
-
Interaction between pathogenic proteins in neurodegenerative disorders.J Cell Mol Med. 2012 Jun;16(6):1166-83. doi: 10.1111/j.1582-4934.2011.01507.x. J Cell Mol Med. 2012. PMID: 22176890 Free PMC article. Review.
-
Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA.Proc Natl Acad Sci U S A. 2024 Jul 16;121(29):e2321408121. doi: 10.1073/pnas.2321408121. Epub 2024 Jul 8. Proc Natl Acad Sci U S A. 2024. PMID: 38976730 Free PMC article.
-
Basic mechanisms of neurodegeneration: a critical update.J Cell Mol Med. 2010 Mar;14(3):457-87. doi: 10.1111/j.1582-4934.2010.01010.x. Epub 2010 Jan 11. J Cell Mol Med. 2010. PMID: 20070435 Free PMC article. Review.
References
-
- Forman MS, Trojanowski JQ, Lee VM. Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med. 2004;10:1055–1063. - PubMed
-
- Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med. 2004;10(Suppl):S10–17. - PubMed
-
- Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356. - PubMed
-
- Golde TE. Disease modifying therapy for AD? J Neurochem. 2006;99:689–707. - PubMed
LinkOut - more resources
Full Text Sources
Other Literature Sources