“That there’s some kind of link between telomere length and the risk of Alzheimer’s disease is nothing new in itself, but it was thought that it was down to other underlying commonalities… we’ve been able to show that the telomeres are involved in the actual active mechanism behind the development of the disease, which is completely new and very interesting.”
– Dr. Sara Hägg, docent of molecular epidemiology.
Plaques and tangles disfigure the brains of Alzheimer’s patients almost beyond recognition. They are the stomach-churning effects of a horrific disease, one that has resisted the best efforts of thousands of dedicated researchers. As new ground is broken and new plans of attack created, there are bright bursts of hope for preventing, managing and one day curing Alzheimer’s and other neurodegenerative diseases. Integrated Health Systems and Maximum Life Foundation are pioneering a study to explore them. Please click here to learn more.
So far, most researchers have honed in on a single feature, like beta- amyloid plaque, damaged mitochondria, or Tau tangles in AD. As it accounts for 70% of dementias, AD is the most widely known and intensely researched, but it likely shares common causes with vascular, mixed, and Lewy Body dementias. To address AD and other dementias, Michael Fossel, a renowned expert in the field of telomere biology, has proposed taking a systems approach to understanding dementia, one where cellular senescence is front and center (Fossel, 2020).
An article recently published by Integrated Health Systems explained why cells need telomeres to safely divide, preventing them from becoming senescent. Senescent cells create a proinflammatory environment and are implicated in a host of issues (Van Deursen, 2014). Recently, attempts have been made to create a model of neurodegenerative disorders with the underpinning molecular processes (like telomere shortening) of aging in mind.
The accumulation of beta-amyloid plaques is a hallmark of Alzheimer’s disease. Microglia, the brain’s resident immune cells, appear to facilitate clearance of beta-amyloid. Thus, something that fortifies microglia can help (Hansen, 2017).
In 2016 Dr. Hägg warned against searching for silver bullets. Although, even when she was writing, telomere shortening was already implicated in cognitive impairment, amyloid accumulation, and the hyperphosphorylation of Tau (Zhang, 2015). Yes, maybe these are just correlations. Maybe telomere shortening plays a small causal role. However, since then, we’ve constructed a more detailed picture of AD and other dementias. The importance of telomeres, and by extension, the promise of telomerase induction for an “Alzheimer’s gene therapy” becomes more apparent.
How can telomerase help with neurodegenerative disease? After all, brain cells generally don’t divide. Although, in some regions of the brain it is critical that they do. The recently settled – nearly settled – controversy over adult neurogenesis, the production of new brain cells, is relevant (Tobin, 2019). One area where neurogenesis occurs, and where its continued occurrence is crucial to brain health, is the hippocampus. The hippocampus is crucial for learning and storing new information. Even subtle changes in hippocampal neurogenesis may have a wide-ranging impact on the development and progression of Alzheimer’s disease (Mu, 2011).
While telomere shortening may hasten the decline of neurogenesis, there are not enough studies to make any bold claims about it yet. In mice, exercise increases telomerase expression and neurogenesis (Wolf, 2011). This is exciting, but not nearly as clear as what telomerase can do for astrocytes and microglia, for which there is a sizable and mounting body of evidence.
Immune dysregulation is largely due to cellular senescence. It has been observed that telomere shortening in T Cells is correlated with the level of progression of AD (Panossian et. al, 2003) and, more recently, the senescence of Natural Killer Cells has been suggested as a biomarker of AD progression (Solana, 2018).
An increasing amount of emphasis has been placed on inflammation and oxidative damage over the last decade, specifically inflammation and oxidative damage arising from astrocyte and microglia dysfunction. Connections between Alzheimer’s and inflammation were made decades ago (Akiyama, 2000). Strong correlations between microglial activation and cognitive decline have also been noticed (Cagnin et al. 2001; Versipt et. al. 2003).
Interest in telomerase to address neurodegenerative disorders like Alzheimer’s and Parkinson’s comes from its effects on astrocytes and microglia. Astrocytes are the most abundant cells in the nervous system. They are also among the most versatile, having a score of duties. In the context of neurodegenerative disease their most notable job is shielding neurons from oxidative damage. It’s no surprise that astrocyte dysfunction is involved in AD and Huntingon’s chorea. It’s also been hypothesized that the neuronal toxicity from astrocyte dysfunction contributes to Parkinson’s disease (Booth, 2017).
Hansen et. al have constructed a narrative about microglia’s role in Alzheimer’s disease. Ordinarily the brain’s dutiful custodians, cleaning out beta-amyloid and maintaining tissue homeostasis. However, over time (perhaps with some help from genetic predispositions such as APOE variants), they become incapable of dealing with their workload. As beta-amyloid plaques reach toxic levels, Tau pathology begins damaging neurons. This overactivates the microglia, leading a proinflammatory environment. Glial cells were largely ignored for years, but investigations into genes expressed mostly or only by glial cells has overturned this way of thinking (Hemmenot, 2019).
Restoring telomere length to glial cells is one way we could ward off a number of neurodegenerative diseases or, at the very least, reduce our chances of developing dementia while staving off “normal” age-related cognitive decline. Given the wide ranging benefits of telomerase, it would be one of the first “vaccines” that could confer protection from a disease (several, actually) while also having a host of other positive effects on human health.
Akiyama, Haruhiko, et al. “Inflammation and Alzheimer’s disease.” Neurobiology of aging 21.3 (2000): 383-421.
Booth, Heather DE, Warren D. Hirst, and Richard Wade-Martins. “The role of astrocyte dysfunction in Parkinson’s disease pathogenesis.” Trends in neurosciences 40.6 (2017): 358-370.
Blackburn, Daniel, et al. “Astrocyte function and role in motor neuron disease: a future therapeutic target?.” Glia 57.12 (2009): 1251-1264.
Cagnin, Annachiara, et al. “In-vivo measurement of activated microglia in dementia.” The Lancet 358.9280 (2001): 461-467.
Collado, Manuel, Maria A. Blasco, and Manuel Serrano. “Cellular senescence in cancer and aging.” Cell 130.2 (2007): 223-233.
Mu, Yangling, and Fred H. Gage. “Adult hippocampal neurogenesis and its role in Alzheimer’s disease.” Molecular neurodegeneration 6.1 (2011): 85.
Hansen, David V., Jesse E. Hanson, and Morgan Sheng. “Microglia in Alzheimer’s disease.” Journal of Cell Biology 217.2 (2017): 459-472.
Hemonnot, Anne-Laure, et al. “Microglia in Alzheimer disease: Well-known targets and new opportunities.” Frontiers in aging neuroscience 11 (2019): 233.
Hochstrasser, Tanja, Josef Marksteiner, and Christian Humpel. “Telomere length is age-dependent and reduced in monocytes of Alzheimer patients.” Experimental gerontology 47.2 (2012): 160-163.
“Telomere Length Shortening and Alzheimer Disease – A Mendelian Randomization Study” JAMA Neurol. 2015;72(10):1202-1203, online first 12 October 2015, DOI: 10.1001/jamaneurol.2015.1513
Panossian, L. A., et al. “Telomere shortening in T cells correlates with Alzheimer’s disease status.” Neurobiology of aging 24.1 (2003): 77-84.
staff, Science X. “Causal Link between Telomere Shortening and Alzheimer’s Disease.” Medical Xpress – Medical Research Advances and Health News, Medical Xpress, 13 Oct. 2015, medicalxpress.com/news/2015-10-causal-link-telomere-shortening-alzheimer.html
Siracusa, Rosalba, Roberta Fusco, and Salvatore Cuzzocrea. “Astrocytes: role and functions in brain pathologies.” Frontiers in pharmacology 10 (2019): 1114.
Tobin, Matthew K., et al. “Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer’s Disease Patients.” Cell stem cell 24.6 (2019): 974-982.
Versijpt, Jan J., et al. “Assessment of neuroinflammation and microglial activation in Alzheimer’s disease with radiolabelled PK11195 and single photon emission computed tomography.” European neurology 50.1 (2003): 39-47.
Wolf, Susanne A., Andre Melnik, and Gerd Kempermann. “Physical exercise increases adult neurogenesis and telomerase activity, and improves behavioral deficits in a mouse model of schizophrenia.” Brain, behavior, and immunity 25.5 (2011): 971-980.
Zhao, Ruohe, et al. “Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease.” Molecular neurodegeneration 12.1 (2017): 47.
Zhang, Jianmin, et al. “Telomere dysfunction of lymphocytes in patients with Alzheimer disease.” Cognitive and Behavioral Neurology 16.3 (2003): 170-176.
