Brain Ponderings podcast with Dr. Mark Mattson

In this lecture I describe how changes occurring in the brain during normal aging set contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Cellular and molecular hallmarks of aging predispose brain cells to neurodegenerative orders with environmental and genetic factors determining if and when the disease manifests. LINKS: Review articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC3710114/pdf/nihms288391.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC7948516/pdf/nihms-1624328.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC9242841/pdf/nihms-1685119.pdf

During the past decade several new technological advances have enabled the identification of ensembles of neurons that encode a specific memory trace (engram cells) and for controlling the activity of engram cells so that recall or inhibition of a memory is controlled by the experimenter. The technologies include fluorescence 'tagging' of engram cells and optogenetic activation or inhibition of the engram cells. In this episode professor Tomás Ryan talks about these developments and his own research which provides evidence that memory recall involves competition between different engrams, that forgetting a memory is an active process in which recall of the memory is suppressed. Studies of amnesia have shown that memory engrams can still exist and can be recalled by electrical stimulation. LINKS Review and Perspective articles https://www.cell.com/action/showPdf?pii=S0166-2236%2825%2900153-5 file:///Users/markmattson/Downloads/s41583-021-00548-3%20(1).pdf Engram cell connectivity and memory https://www.cell.com/action/showPdf?pii=S0960-9822%2823%2901512-9 Forgetting and engram expression https://pmc.ncbi.nlm.nih.gov/articles/PMC11537488/pdf/elife-92860.pdf

Recent discoveries show that some neurodegenerative disorders occur because of abnormalities in the processing of RNA in the cell nucleus and/or its export from the nucleus. Johns Hopkins University Associate Professor Shuying Sun is at the forefront of research that is establishing the molecular mechanisms responsible for RNA dysregulation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Her research is contributing to a rapid acceleration of understanding of the causes of ALS and FTD and to the development of new pharmacological and gene therapy-based treatments for these disorders. LINKS Dr. Sun's laboratory webpage: https://sunlab.jhmi.edu/ Review article https://pmc.ncbi.nlm.nih.gov/articles/PMC11790913/pdf/44318_2024_Article_352.pdf Original research articles https://pmc.ncbi.nlm.nih.gov/articles/PMC5754368/pdf/41467_2017_Article_2495.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC6895427/pdf/nihms-1539444.pdf https://www.biorxiv.org/content/10.1101/2025.09.30.679260v1 https://www.biorxiv.org/content/10.1101/2025.09.30.679260v1 https://www.biorxiv.org/content/10.1101/2025.06.13.659508v1

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel. This episode begins by highlighting recent evidence showing adverse effects on the brain of excessive activation of the mTOR pathway as a consequence of dietary branched chain amino acid consumption. Then I describe evidence that Beyond the age of 40 years brain aging results in progressive decrements in function which are associated with reductions in gray matter and synapse numbers particularly in brain regions that play critical roles in memory, executive functions, and task switching. Recent progress has been made in identifying molecular markers of brain aging in samples of blood or cerebrospinal fluid heralding a better understanding of factors that accelerate or retard brain aging. This episode reviews some of the salient research in these areas.

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel. This video describes 12 major changes that occur in brain cells during aging and their involvement in decline in brain function and the development of neurodegenerative disorders including dementia and Parkinson's disease.

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel. This is the first of five lectures on the Neurobiology of Aging. The other four lectures cover cellular hallmarks, structural and functional aspects, biomarkers, how neurodegenerative disorders occur during aging, and how aging can be slowed and brain health span extended by lifestyle and dietary changes.

The lipid membrane bilayer of cells is composed of fats including phospholipids, cholesterol, and sphingomyelin. Enzymes called sphingomyelinases can cleave sphingomyelin resulting in the liberation of ceramides which can diffuse within the cell and act as signaling molecules. In this episode I talk with Tulane University Professor Norm Haughey about research in his laboratory and others which have shown that levels of certain ceramides are increased in the brain, cerebrospinal fluid, and blood of patients with Alzheimer's disease, HIV-associated cognitive disorder, and other neurological disorders. Elevated ceramides may provide a biomarker for individuals at risk for these disorders. Dr. Haughey and his collaborators have shown that drugs that inhibit a particular sphingomyelinase can prevent degeneration of neurons and associated cognitive impairment in animal models of Alzheimer's disease and HIV. Norm Haughey's laboratory webpage: https://haugheylab.org/ Relevant articles https://pmc.ncbi.nlm.nih.gov/articles/PMC2907186/pdf/nihms-209661.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC2933928/pdf/nihms200180.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC3144420/pdf/nihms309072.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC3414665/pdf/znl633.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC7852391/pdf/aba5210.pdf https://www.sciencedirect.com/science/article/pii/S0969996123000013?via%3Dihub https://pmc.ncbi.nlm.nih.gov/articles/PMC10334757/pdf/pnas.202219543.pdf

Brain tumor cells interact with neurons, glial cells, and immune cells in complex ways that often benefit the cancer cells while compromising the function of normal neural cells. In this episode I talk with Washington University Neurology Professor David Gutmann about brain cancer cells and their communication with surrounding normal cells. A major component of Dr. Gutmann's research program focuses on Neurofibromatosis a rare genetic disorder that causes non-malignant brain tumors as well as abnormal growth of cells in other organ systems. The disease results from loss-of-function mutations in the NF1 protein which normally functions to constrain cell growth. Discoveries concerning the 'sociobiology' of brain tumors is providing a foundation for the development of new approaches for treating a range of cancers. LINKS Dr. Gutmann's Wikipedia page: https://en.wikipedia.org/wiki/David_H._Gutmann Related articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC10107403/pdf/nihms-1872327.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC9883043/pdf/nihms-1861630.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC11972679/pdf/djae249.pdf

There is considerable evidence that exposure to certain chemicals in the environment cause Parkinson's disease in many people. In this episode neurologist Ray Dorsey talks about some of the chemicals that may cause Parkinson's disease including the pesticides paraquat and rotenone, and trichloroethylene and perchloroethylene which are chemicals used for degreasing and dry-cleaning. LINKS Relevant journal articles: https://www.thelancet.com/action/showPdf?pii=S1474-4422%2825%2900287-X file:///Users/markmattson/Downloads/Annals%20of%20Neurology%20-%202008%20-%20Gash%20-%20Trichloroethylene%20%20Parkinsonism%20and%20complex%201%20mitochondrial%20neurotoxicity%20(1).pdf Book on how to reduce one's risk for Parkinson's disease: https://www.amazon.com/Parkinsons-Plan-Path-Prevention-Treatment/dp/1541705386/ref=sr_1_1?adgrpid=186412556077&dib=eyJ2IjoiMSJ9.8jetPIdc_D3gQSod-GXEVDXUJcI1IMKFz7jXpUf0jZt-LxGsRBm9oV9TQGQJK_FDpWNY4KOJrayE8WoGPJsMXbouqzGwj3UhO0CZZGHmz8g.M4hWGhlS7Crp9zwfODlDDDNnseiHLTdHHBLooZ1LR-M&dib_tag=se&hvadid=779621628364&hvdev=c&hvexpln=0&hvlocphy=9007816&hvnetw=g&hvocijid=14825241056223650898--&hvqmt=b&hvrand=14825241056223650898&hvtargid=aud-2443140936121%3Akwd-936298351901&hydadcr=15520_13558534_8423&keywords=ray+dorsey+parkinson&mcid=c3eec2c85d703461a8216f138ac2c1e7&qid=1762952366&sr=8-1#averageCustomerReviewsAnchor

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