A shared feature of neurodegenerative disorders is accumulation of aggregated proteins within neurons: Tau in Alzheimer's disease; alpha-synuclein in Parkinson's disease; huntingtin in Huntington's disease; and TDP43 in amyotrophic lateral sclerosis. In this episode Ai Yamamoto – an Associate Professor Neurology at Columbia University – talks about the trail of discoveries that led to the identification of a protein called ALFY that can prevent and reverse the accumulation of such pathogenic proteins. Remarkably, her team and collaborators found that some people have a variant of the gene encoding ALFY that confers resistance of those individuals to Huntington's disease. This discovery opens many new and exciting directions for future research aimed at better understanding what goes wrong in neurodegenerative disorders and for developing interventions counteract the disease process.

LINKS

Yamamoto Laboratory web page: https://www.aiyamamoto-lab.org/

Dr. Yamamoto's publications: https://scholar.google.com/citations?hl=en&user=HuJslgMAAAAJ&pagesize=80&view_op=list_works

Key research articles:

https://www.cell.com/action/showPdf?pii=S0896-6273%2825%2900624-5

file:///Users/markmattson/Downloads/s41583-022-00588-3.pdf

https://www.cell.com/action/showPdf?pii=S0896-6273%2819%2931045-1

Remarkable advances are being made in the development and clinical applications of stimulation devices that enable recovery of motor function in patients who have suffered a spinal cord injury, a stroke, and even those with rare disabling genetic disorders. At the forefront of this research is Marco Capogrosso at the University of Pittsburgh. He has shown that certain patterns of stimulation of sensory pathways in the spinal cord can activate motor neurons that were otherwise silenced by the injury or stroke. Initial clinical trials have shown that this approach results in recovery of function which are in some cases very dramatic in patients that have had a stroke, a spinal cord injury, and in people with the genetic disorder spinal muscular atrophy. In this episode Dr. Capogrosso talks about the development of this stimulation-based therapeutic approach, the clinical trials, and the potential applications of this technology to other neurodegenerative disorders.

LINKS

Dr. Capogrosso's profile at the University of Pittsburgh:

https://www.neurosurgery.pitt.edu/people/marco-capogrosso

Key studies discussed in this podcast:

Stroke

https://pmc.ncbi.nlm.nih.gov/articles/PMC10291889/pdf/nihms-1904547.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12393459/pdf/nihpp-rs7271578v1.pdf

Spinal cord injury

https://pmc.ncbi.nlm.nih.gov/articles/PMC5108412/pdf/emss-70056.pdf

https://www.cell.com/neuron/fulltext/S0896-6273(25)00658-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627325006580%3Fshowall%3Dtrue#

Spinal muscular atrophy

https://www.nature.com/articles/s41591-024-03484-8

Dietary iron is essential for health as it plays important roles in the ability of hemoglobin to carry oxygen throughout the body and brain. In addition, iron is involved in various functions in cells including the generation of ATP in mitochondria and DNA synthesis. The vast majority of iron is bound to proteins such as ferritin and heme. However, in its ionic form (Fe2+) iron can react with the hydrogen peroxide produced from mitochondrial superoxide radical to generate the highly toxic hydroxyl radical. Hydroxyl radical damages DNA and can also act on the carbon=carbon double bonds in unsaturated member lipids and trigger an autocatalytic process called lipid peroxidation. Lipid peroxidation in neurons occurs in Alzheimer's and Parkinson's disease and may play a major role in the death of neurons in these disorders a process called 'ferroptosis'. In this episode I talk with Scott Ayton a Professor at the Florey Institute at the University of Melbourne about both the normal functions of iron in neurons, its involvement in Alzheimer's and Parkinson's disease, and the potential of interventions that prevent ferroptosis in the treatment of these disorders.

LINKS

Professor Aytons profile at the Florey Institute:

https://florey.edu.au/researcher/scott-ayton/

Relevant articles

file:///Users/markmattson/Downloads/s41583-025-00930-5%20(1).pdf

https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1196/annals.1306.004?saml_referrer

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2209254

https://jamanetwork.com/journals/jamaneurology/article-abstract/2825846

Health depends upon proper regulation of circadian rhythms of cell and organ functions. Disruption of circadian rhythms has detrimental consequences for brain function and resilience and abnormal circadian rhythms are a common feature of Alzheimer's disease. In this episode neurology professor Erik Musiek talks about the roles of specific circadian clock proteins in neurons and glial cells in brain health and Alzheimer's disease. His research is revealing the ways in which these circadian regulatory proteins affect brain cell functions and how disruption of circadian rhythms may contribute to the neuropathological features of Alzheimer's disease (amyloid plaques and neurofibrillary tangles. We also talk about ways in which we can bolster our circadian rhythms by sleep, exercise, diet, light exposure, etc.

LINKS

Professor Musiek's webpage: https://physicians.wustl.edu/people/erik-musiek-md-phd/

Articles discussed in this podcast:

https://pmc.ncbi.nlm.nih.gov/articles/PMC12352436/pdf/nihms-2097957.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC11996435/pdf/nihpp-2025.03.31.645805v1.pdf

https://www.nature.com/articles/s43587-025-00950-x

https://pmc.ncbi.nlm.nih.gov/articles/PMC9008766/pdf/nihms-1794994.pdf

Chronic uncontrolled stress is a risk factor for many different diseases including mental and neurodegenerative disorders. The effects of such stress on the brain differ considerably between females and males. However, the vast majority of preclinical studies in animal models have included only males which in some cases has resulted in therapeutic interventions that are less effective in females compared to males. In this episode Georgia Hodes talks about sex differences in the effects of stress on the brain and neuroendocrine systems and how these differences can influence disease processes and treatments.

LINKS

Prof. Hodes webpage at VT:

https://neuroscience.vt.edu/our-people/research-faculty/hodes-georgia.html

Review articles:

https://pmc.ncbi.nlm.nih.gov/articles/PMC10845083/pdf/CN-22-475.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC10189838/pdf/nihms-1896436.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC8630768/pdf/nihms-1528739.pdf

In stressful situations the brain communicates with the adrenal glands stimulating them to release adrenaline and cortisol. This stress responsive neuroendocrine system plays important adaptive roles by regulating energy metabolism, attention, and learning and memory. However, without a recovery period chronic uncontrolled stress such as psychosocial stress can damage neural circuits in the brain and contribute to a range of mental disorders as well as Alzheimer's disease. In this episode I have the pleasure of talking with two pioneers in the field of stress research – Professors Marian Joëls and Ron de Kloet. Their work which spans five decades has shown how two different cortisol receptors determine how the brain responds to physiological and pathological stress. They have revealed how a "cortisol switch" determines brain vulnerability or resilience.

Links

Marian Joëls' webpage: https://www.rug.nl/staff/m.joels/cv

Ron de Kloet publications on Google Scholar: https://scholar.google.com/citations?user=Eao7yZIAAAAJ&hl=en&oi=ao

The "Cortisol Switch"

file:///Users/markmattson/Downloads/s41380-022-01934-8.pdf

https://www.sciencedirect.com/science/article/pii/S0091302218300116?via%3Dihub

Clearly demonstrated as being effective for cardiovascular disease, lifestyle medicine is becoming an important discipline for the prevention and treatment of age-related brain disorders including Alzheimer's and Parkinson's diseases. In this episode I talk with Dr. Josh Helman about his experience working with patients at lifestyle medicine centers. He provides his views on what people can do now to reduce their risk for these brain disorders, and what the future holds in terms of therapeutic interventions.

LINKS

Dr. Helman's webpage: https://drjosh.com/

Lifestyle medicine approach: https://pmc.ncbi.nlm.nih.gov/articles/PMC10907160/pdf/main.pdf

The calcium ion controls neuronal network activity, synapse function and synaptic plasticity, and is a fundamental mediator of learning and memory. With aging and much more so in Alzheimer's disease the ability of neurons to properly regulate their intracellular calcium levels becomes compromised. Evidence from human and laboratory animal studies have provided compelling evidence that excessive elevation of calcium levels in neurons results in their dysfunction and degeneration in Alzheimer's disease, as well as in Parkinson's disease, and stroke. In this episode, I talk with Professor Beth Stutzmann about her research which has advanced an understanding about how calcium regulation becomes disrupted in neurons in Alzheimer's disease. Her findings point to excessive release of calcium from intracellular pools (in the endoplasmic reticulum) as being particularly important in Alzheimer's. This research points to new therapeutic interventions for this devastating disease.

LINKS

Stutzmann laboratory: https://www.rosalindfranklin.edu/academics/faculty/grace-e-stutzmann/

Relevant articles:

https://pmc.ncbi.nlm.nih.gov/articles/PMC7763805/pdf/cells-09-02655.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC9894236/pdf/pnas.202211999.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12305934/pdf/40478_2025_Article_2023.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC3091392/pdf/nihms288394.pdf