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Alzheimer's

Unlocking New Therapeutic Advances for Heart and Alzheimer’s Disease: The Discovery of a Novel Mitochondrial Protein

Calcium transport into and out of mitochondria — the powerhouses of cells — is central to cellular energy production and cell death. To maintain the balance of calcium within these powerhouses, cells rely on a protein known as the mitochondrial sodium-calcium exchanger, or NCLX. Now, in new research, scientists have discovered a novel regulator of NCLX activity, a protein called TMEM65, which helps move calcium out of mitochondria, protecting against harmful calcium overload.

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The discovery of TMEM65, a novel mitochondrial protein regulator of NCLX activity, has opened up new possibilities for therapeutic advances in treating conditions such as heart failure and Alzheimer’s disease. Researchers at the Lewis Katz School of Medicine at Temple University have found that TMEM65 plays a critical role in maintaining the balance of calcium within mitochondria, protecting against harmful calcium overload.

Mitochondrial calcium exchange is essential for regulating cell survival and pro-energetic signaling pathways. When mitochondria take in too much calcium, energy metabolism is disrupted, and cells die. This is most apparent in the heart, where calcium overload contributes to the permanent loss of heart muscle cells during heart attacks and in heart failure. Similarly, it can result in the loss of brain cells in Alzheimer’s disease and other neurodegenerative conditions.

The research, published in the journal Nature Metabolism, describes the first characterization of the interaction of TMEM65 with NCLX in mitochondria. “TMEM65 is the first protein identified that is a bona fide interactor and regulator of NCLX,” explained Dr. John W. Elrod, W.W. Smith Chair in Cardiovascular Medicine and Founding Director of the Aging + Cardiovascular Discovery Center at the Lewis Katz School of Medicine.

The discovery was made possible by using biotin tagging, which allowed researchers to trace NCLX’s interactions with other proteins in intact cells. The fusion protein was then placed back into cells, and other proteins that came within its proximity were biochemically labeled. This led to the identification of TMEM65 as a primary suspect in NCLX regulation.

Subsequent experiments revealed that when TMEM65 is removed from cells, calcium levels in the mitochondria accumulate, leading to cell death. The role of TMEM65 was confirmed in a mouse model where TMEM65 levels were significantly decreased, resulting in progressive loss of neuromuscular function as animals matured.

The methods used to identify TMEM65 and elucidate NCLX regulation are groundbreaking in the field of basic cardiovascular science. Dr. Elrod and colleagues plan next to explore the possibility of modulating TMEM65 activity as a therapeutic strategy.

This discovery exemplifies the transformative science happening at the Lewis Katz School of Medicine, where researchers are paving the way for innovative treatments that could have a profound impact on patients with heart failure, Alzheimer’s disease, and beyond.

Alzheimer's

The Surprising Link Between Curiosity and Healthy Aging

Psychology literature has shown that curiosity tends to decline with age. Psychologists shows one type of curiosity can increase well into old age, contradicting prior research. Older adults who maintain curiosity and want to learn new things relevant to their interests may be able to offset or even prevent Alzheimer’s disease. Conversely, those who show muted curiosity and disinterest may be at risk for dementia.

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The secret to aging successfully may not be what you think. Instead of focusing on physical exercise or mental stimulation alone, research suggests that cultivating curiosity can play a significant role in maintaining cognitive health and even preventing Alzheimer’s disease. An international team of psychologists has found that older adults who maintain a curious mindset and seek out new knowledge relevant to their interests may be able to offset or prevent dementia.

This finding challenges prior research that suggested curiosity decreases with age. The study, published in the journal PLOS One, was led by UCLA psychologist Alan Castel and involved a large sample of participants between the ages of 20 and 84. The researchers aimed to tease apart two types of curiosity: trait curiosity (a general level of inquisitiveness) and state curiosity (a momentary feeling of curiosity experienced when engaging with specific topics).

To assess these forms of curiosity, the researchers asked participants to complete an online questionnaire and guess answers to hard trivia questions. Analysis showed that while trait curiosity did decline across the adult lifespan, state curiosity increased sharply after middle age and continued upward well into old age.

The study’s lead author, Mary Whatley, notes that this finding may be related to selectivity theory, which suggests that as people get older, they become more selective about what they want to learn. This aligns with research on lifelong learning, where many older adults engage in activities like taking classes or picking up hobbies.

Castel’s own work on memory has shown that people tend to quickly forget information that doesn’t engage their curiosity. Anecdotally, many older adults report that staying curious is crucial for maintaining cognitive health and preventing dementia.

This study was supported by the National Institutes of Health’s National Institute on Aging, the Leverhulme Trust, and the Alexander von Humboldt Foundation. The findings suggest that cultivating curiosity can be a key factor in healthy aging and may even help prevent or offset Alzheimer’s disease.

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Alzheimer's

“Unlocking Brain Resilience: Researchers Discover CLU Protein’s Potential to Protect Against Alzheimer’s Disease”

Recently approved Alzheimer’s drugs offer a step forward for treating the disease, but new therapeutic strategies are needed to complement them and provide personalized therapeutic approaches. Researchers have identified a potential strategy to protect against Alzheimer’s disease by increasing the clusterin protein (CLU).

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As scientists continue to search for effective treatments for Alzheimer’s disease, a recent study has shed light on a promising new approach. Researchers at Mass General Brigham have discovered that increasing levels of the “CLU” (clusterin) protein may protect against cognitive decline and potentially provide a complementary therapy to existing treatments.

Led by Dr. Tracy Young-Pearse, the research team used various models, including human brain tissue from over 700 participants and animal models, to uncover the molecular role of CLU in protecting against neurodegeneration. Their findings suggest that increasing CLU can prevent inflammatory interactions between brain cells called astrocytes and microglia, which are associated with heightened inflammation.

The study’s results have significant implications for the design and testing of new therapeutic strategies for Alzheimer’s disease. As Dr. Young-Pearse noted, “Increasing clusterin has the potential to prevent cognitive decline in a way that is different than and complementary to anti-amyloid therapies to promote brain resilience.”

CLU may also be beneficial for treating other age-related brain diseases, many of which share similar mechanisms of neuroinflammatory dysregulation. The researchers emphasize the importance of personalized therapeutic approaches, as individuals’ responses to CLU upregulation vary based on their genetics.

The study’s findings provide a crucial step forward in the search for effective treatments for Alzheimer’s disease and other age-related brain diseases. By understanding the role of CLU in protecting against neurodegeneration, researchers can develop new strategies to promote brain resilience and potentially prevent cognitive decline.

In conclusion, the discovery of CLU’s potential therapeutic benefits offers new hope for individuals affected by Alzheimer’s disease and other age-related brain disorders. Further research is necessary to fully explore this promising approach, but the findings of this study mark an important milestone in the pursuit of effective treatments for these debilitating diseases.

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Alzheimer's

Physical Activity in Middle Age May Help Prevent Alzheimer’s Disease

An increase in physical activity between the ages of 45 and 65 could help prevent Alzheimer’s disease, while inactivity may be detrimental to brain health.

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Physical Activity in Middle Age May Help Prevent Alzheimer’s Disease

A recent scientific study has shed light on the importance of physical activity in middle age for preventing Alzheimer’s disease. The research, published in Alzheimer’s & Dementia, highlights the need to promote physical activity among adults aged 45-65.

The study found that increasing physical activity during this period can help prevent Alzheimer’s disease, while a sedentary lifestyle may be detrimental to brain health. In fact, it is estimated that 13% of Alzheimer’s disease cases worldwide can be attributed to physical inactivity.

The World Health Organization (WHO) recommends at least 150-300 minutes of moderate activity per week or 75-150 minutes of vigorous activity per week. While extensive research has shown that exercise reduces the risk of Alzheimer’s disease by improving cardiovascular and mental health, this study suggests that physical activity may have a direct impact on the development of brain pathology associated with the disease.

The research team conducted a four-year follow-up of middle-aged residents of Catalonia with a family history of Alzheimer’s disease. Participants were classified as adherent (meeting WHO recommendations), non-adherent (doing less than the recommended amount of physical activity), and sedentary (doing zero minutes of physical activity per week).

The study found that participants who increased their physical activity to meet WHO-recommended levels showed less beta-amyloid accumulation, a protein that can impair neural communication when it accumulates in the brain. Moreover, this effect appeared to be dose-dependent; the greater the increase in activity, the greater the reduction in amyloid burden.

Non-sedentary participants also showed a greater cortical thickness in brain regions associated with Alzheimer’s disease. Cortical thickness is crucial for memory, and its thinning or atrophy (loss of volume) is an early sign of neurodegeneration.

“The findings reinforce the importance of promoting physical activity in middle age as a public health strategy for Alzheimer’s prevention,” emphasizes Eider Arenaza-Urquijo, ISGlobal researcher and lead investigator of the study. “Interventions aimed at promoting increased physical activity could be key to reducing the incidence of the disease in the future.”

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