Brain Ponderings podcast with Mark Mattson

In this episode Emory University and Chinese Academy of Sciences Professor Keqiang Ye talks about his fascinating and ground-breaking trail of discoveries that have revealed previously unknown mechanism responsible for the production and accumulation of damaging fragments of the APP and Tau proteins in Alzheimer’s disease (AD) and the alpha-synuclein protein in Parkinson’s disease (PD). He discovered an enzyme called AEP that cleaves Tau and alpha-synuclein into self-aggregating toxic fragments.  Eliminating or disabling AEP can prevent the disease process and preserve brain function in mouse models of AD and PD.  More recently, in a series of studies his laboratory has provided evidence that the generation of rogue Tau and alpha-synuclein fragments first occurs in neurons surrounding the intestines and then propagates up the vagus nerve to the brain. Moreover, his group has shown that certain species of bacteria in the gut can promote the development of the disease. Finally, Professor Ye has developed drugs that inhibit AEP or activate BDNF receptors as potential treatments for AD and PD.  LINKS Key publications: https://pmc.ncbi.nlm.nih.gov/articles/PMC4224595/pdf/nihms623922.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC5315368/pdf/nihms825673.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC10482867/pdf/41467_2023_Article_41283.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC8408610/pdf/EMBJ-40-e106320.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC6951265/pdf/41422_2019_Article_241.pdf Professor Ye’s Google Scholar page: https://scholar.google.com/citations?user=VSP72CMAAAAJ&hl=en

Among high income countries the United States spends the most on health care and yet has the lowest life expectancy. A high percentage of Americans suffer with chronic diseases including obesity, diabetes, cardiovascular disease, mental disorders, and Alzheimer’s or Parkinson’s diseases. There are several reasons why people living in the wealthiest country have poor health all attributable to unrestrained capitalism. In this episode I talk about issues with pharmaceutical industry that contribute to the overall poor quality of health and health care in America with a focus on drugs for neurological disorders.  Drug prices in the US are much higher than in other countries and prices are increasing at a rate more than 5 times the rate of inflation. Pharmaceutical companies spend nearly twice as much on marketing as on research and development and overstate their costs for drug development by ~400 percent. The US is one of only two countries that permit direct advertising of drugs to consumers. Pharmaceutical company representatives lobby doctors and congress.  There are also major issues concerning clinical trials of drugs including conflicts of interest, lack of data transparency, and lack of head-to-head comparisons of a new drug with an existing drug. There are potential solutions to these problems but will require major new government regulations. https://pubmed.ncbi.nlm.nih.gov/31034803/ https://pmc.ncbi.nlm.nih.gov/articles/PMC8649053/pdf/nihms-1751070.pdf

In this episode I talk with Professor Jason Shepherd about his discoveries concerning a fascinating protein called Arc.  In response to synaptic activity Arc levels rapidly increase in postsynaptic dendrites as a result of local translation of the Arc mRNA in the dendrites. Arc plays a critical role in long-term memory although it is not necessary for learning. But perhaps the most interesting twist in the Arc story comes from the Shepherd labs discovery that Arc can self-assemble into highly ordered structures that are essentially identical to the capsids that form the coat of viruses. I talk with Jason about evidence that Arc can bind mRNAs and transfer them from one neuron to another in extracellular vesicles. These findings reveal a whole new mechanism for regulating neuronal network function. Moreover, recently Jason and his lab members have demonstrated a key role for Arc in the trans-neuronal propagation of Tau pathology which is an important advance in understanding how the neurodegenerative process spreads throughout neuronal networks in Alzheimer’s disease and other neurodegenerative disorders – and also has implications for novel approaches for halting the disease process.  LINKS: The Shepherd laboratory page: https://www.shepherdlab.org/ Key publications from the Shepherd lab: https://pmc.ncbi.nlm.nih.gov/articles/PMC8041237/pdf/nihms-1661230.pdf https://www.cell.com/action/showPdf?pii=S0092-8674%2817%2931504-0 https://pmc.ncbi.nlm.nih.gov/articles/PMC11526995/pdf/nihpp-2024.10.22.619703v1.pdf

Among high income countries the United States spends the most on health care and yet has the lowest life expectancy. A high percentage of Americans suffer with chronic diseases including obesity, diabetes, cardiovascular disease, mental disorders, and Alzheimer’s or Parkinson’s diseases. There are several reasons why people living in the wealthiest country have poor health all attributable to unrestrained capitalism.  In this episode I talk about how large-scale monoculture crops used to produce addictive ultraprocessed sugars such as high fructose corn syrup adversely affect health including brain health. The widespread availability of such obesogenic high-calorie ultraprocessed foods at low prices have propelled a transgenerational epidemic of obesity, diabetes and associated chronic brain disorders. Increasingly sedentary lifestyles exacerbate the problem. In also talk about the health benefits of a range of organically grown vegetables and fruits with a focus on a few specific chemicals they produce that act on cells in ways that bolster their function and resilience.    Here are links to a few articles that provide more detail on the problem and potential solutions. https://pmc.ncbi.nlm.nih.gov/articles/PMC9904196/pdf/nihms-1868184.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC8748512/pdf/41467_2021_Article_27645.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC6779523/pdf/nihms-1537205.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC5841445/pdf/nihms946635.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC4081729/pdf/pr.113.007757.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC4586293/pdf/nihms678801.pdf

Humans have the amazing ability to instantly recognize the faces of hundreds or even thousands of people they have previously met or seen in pictures or movies. Studies of people with brain injuries that render them incapable of recognizing faces and recordings of neuronal activity in people during face recognition have shown that networks in the occipital and temporal lobes adjacent to the visual cortex mediate facial recognition.  Professor Bruno Rossion is at the forefront of research that is revealing the neurophysiological underpinnings of face recognition. By recording and stimulating neurons in the face recognition circuits of numerous research participants Rossion’s laboratory has elucidated how the brain captures and recalls the gestalt of a face without dwelling on specific features of the face. LINKS: Review articles on the neurobiology of face recognition: https://pmc.ncbi.nlm.nih.gov/articles/PMC9954066/pdf/brainsci-13-00354.pdf https://www.sciencedirect.com/science/article/pii/S0028393224000800?via%3Dihub https://www.sciencedirect.com/science/article/pii/S0149763424000034?via%3Dihub  

In this final episode of the Bioenergetics and Brain Health series I talk about changes that occur in brain cells during normal aging, and in Alzheimer’s disease, Parkinson’s disease, and stroke with emphasis on alterations upstream and downstream of cellular energy metabolism. The episode concludes with examples of therapeutic interventions that target those age- and disease-related alterations.  LINKS: Hallmarks of Brain Aging https://pmc.ncbi.nlm.nih.gov/articles/PMC6039826/pdf/nihms979409.pdf Brain Energy Rescue: https://pmc.ncbi.nlm.nih.gov/articles/PMC7948516/pdf/nihms-1624328.pdf The Hormesis Principle of Brain Health and Resilience https://pmc.ncbi.nlm.nih.gov/articles/PMC5209274/pdf/nihms834422.pdf

In this third podcast in the Bioenergetics and Brain Health series I talk about how intermittent exercise and fasting affect brain function, neuroplasticity, and resilience. Research has shown that both of these bioenergetic challenges can enhance learning and memory, improve mood, counteract aging, and protect neurons against injury and disease. I provide an overview of evidence that over periods of weeks and months cycling between challenge (exercise and fasting) and recovery (resting, eating, sleeping) periods stimulates the formation of new synaptic connections between neurons, increases neurogenesis, and bolsters neuronal stress resistance.  These adaptations of brain cells to bioenergetic challenges are mediated by hormonal factors released from peripheral organs including ketones, and by changes in gene expression in brain cells. A better understanding of how bioenergetic challenges affect the brain provides a rationale for incorporating exercise and fasting into lifestyles and is also revealing new approaches for pharmacological interventions in neurological disorders.

Dive into the fascinating world of mitochondria and their crucial role in brain function! Discover how these energy powerhouses are distributed within neurons, and learn about their processes of division, fusion, and disposal. The podcast highlights the significant impact of physical exercise and intermittent fasting on mitochondrial health and resilience against neurodegenerative diseases. Additionally, explore the interplay of neurotransmitters and calcium dynamics, and how metabolic switching enhances brain energy through ketones.

More than 40 percent of the human genome consists of retrotransposons which are DNA sequences related to retroviruses that can jump within the genome and have the ability to replicate although most are dormant.  In this episode Professor Josh Dubnau at the University of Stony Brook talks about endogenous retroviruses and retrotransposons and recent evidence that some of them are activated in neurons during brain aging and may play roles in the pathogenesis of ALS, frontotemporal dementia, and Alzheimer’s disease. Using the powerful molecular genetic tools in Drosophila models the Dubnau and his team have shown that activated retrotransposons can cause pathological aggregation of the protein TDP43 in neurons and the spreading of the TDP43 pathology between cells similar to that which occurs in ALS and frontotemporal dementia. This basic research advances an understanding of brain aging and neurodegenerative disorders and suggests new approaches for preventing and treating these disorders. LINKS Dr. Dubnau’s web page https://renaissance.stonybrookmedicine.edu/anesthesiology/research/Dubnau Review article on endogenous retroviruses and retrotransposons and their putative roles in neurodegenerative disorders https://pubmed.ncbi.nlm.nih.gov/38663088/ Original research articles https://pmc.ncbi.nlm.nih.gov/articles/PMC9944888/pdf/41467_2023_Article_36649.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC8096092/pdf/pgen.1009535.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC6783360/pdf/nihms-1536529.pdf

This is the fist in a short series of presentations on the interrelationships between energy metabolism, brain function and resilience, and disease processes. Overindulgent sedentary lifestyles are increasingly common with adverse consequences for trajectories of brain health in current and future generations. In this series I review findings from studies of humans and animals that are elucidating the cellular and molecular mechanisms by which energy intake and exercise affect structural and functional neuroplasticity. This topic is considered from a bioenergetic perspective with emphases on brain evolution, developmental neurobiology, adult neuroplasticity and disorders of mood and cognition.