Brain Ponderings podcast with Mark Mattson

Age-related macular degeneration, glaucoma, diabetic retinopathy, and genetic disorders such as retinitis pigmentosa are major causes of blindness. In this episode Professor Russ van Gelder at the University of Washington talks about exciting advances in vision restoration using retinal cell replacement, gene therapy, visual prosthetic devices, and small molecule ‘photoswitches’. Several of these technologies have shown promising results in clinical trials.  LINKS: Review articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10718186/pdf/nihms-1949762.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444397/pdf/nihms-663143.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486303/pdf/nihms-1729966.pdf

The molecular and cellular mechanisms by which the human brain develops cannot be directly studied. Stanford professor Sergiu Pasca is at the forefront of using induced human pluripotent stem cells to establish 3D cultures of individual brain regions (organoids) and multiple interacting brain regions (assembloids). His work has shown that functional neuronal connections can be established and the underlying molecular and cellular regulation of human brain development established.  Human neuroassembloids are also being used to identify the root causes of developmental brain disorders such as autism. LINKS: Human brain organoid and assembloid review: https://www.cell.com/action/showPdf?pii=S0092-8674%2821%2901177-6 Human cortical – spinal cord – muscle neuroassembloid: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8711252/pdf/nihms-1649341.pd  CRISPR screen – developmental brain disorder genes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10567561/pdf/41586_2023_Article_6564.pdf Timothy Syndrome: https://www.cell.com/action/showPdf?pii=S1934-5909%2821%2900483-5

Stroke is the leading neurological cause of disability and death throughout the world and is increasing on the African continent where rates of hypertension are high and Westernized dietary habits are on the rise. At the forefront of the global battle against stroke and other age-related neurological disorders is Mayowa Owolabi, Dean of the Faculty of Clinical Sciences and Director of the Center for Genomic and Precision Medicine at the University of Ibadan, Nigeria.  In this episode Dr. Owolabi talks about the four pillars of reducing the global burden of stroke – epidemiological surveillance; health promotion and disease prevention; acute care; and rehabilitation. While the negative health impacts of profit-driven forces such as the processed food and fossil fuel industries are proving difficult to overcome, considerable progress has been made. Dr. Owolabi talks about the strategies for reducing the global burden of stroke and dementia by implementing bottom-up and top-down approaches.    Stroke in Africa: profile, progress, prospects and priorities. Akinyemi RO et al. .. Owolabi MO. Nature Reviews Neurology. 2021 Oct;17(10):634-656: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441961/pdf/41582_2021_Article_542.pdf Global synergistic actions to improve brain health for human development. Owolabi MO, et al Nature Reviews Neurology 2023 Jun;19(6):371-383: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197060/pdf/41582_2023_Article_808.pdf  

Because neurons are very active cells they consume high amounts of oxygen and produce high amounts of oxygen free radicals (oxyradicals). Because most neurons in the brain exist throughout life and cannot be replaced it is critical that they be able to efficiently remove oxyradicals and repair damage caused to DNA, proteins and membranes caused by oxyradicals. During normal aging and moreso in Alzheimer’s disease neurons accumulate oxidative damaged molecules and mitochondria. In this episode professor George Perry talks about oxidative stress and its roles in synaptic dysfunction and neuronal degeneration in Alzheimer’s disease. He also talks about approaches to preventing and treating Alzheimer’s disease based on holistic rather than targeted interventions.  LINKS: Review articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091392/pdf/nihms288394.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10451948/pdf/antioxidants-12-01628.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452017/pdf/EMBJ-36-1474.pdf

There is currently no effective treatment for Alzheimer’s disease. EEG recordings have shown that gamma frequency electrical oscillations are diminished and aberrant excitatory glutamatergic neurotransmission is increased in the brain’s of people with Alzheimer’s disease.  In this episode MIT Professor Li-Huei Tsai talks about her discovery that gamma frequency (40 Hz) light and sound stimulation can enhance GABAergic inhibitory tone, ameloriate the disease process, and preserve cognition in animal models of Alzheimer’s disease. This research led to initial phase I and II clinical trials of gamma light and sound stimulation in Alzheimer’s disease with encouraging results.  A large phase III trial is in progress. LINKS: Preclinical studies: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774262/pdf/nihms-1538841.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697125/pdf/nihms-1528873.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656389/pdf/nihms886326.pdf   Phase I and II trials in AD patients: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714926/pdf/pone.0278412.pdf   Ongoing phase III trial in AD patients: https://classic.clinicaltrials.gov/ct2/show/NCT05637801?term=cognito&cond=alzheimer%27s&draw=2&rank=1

DNA damage, most often caused by oxygen free radicals, can result in mutations in proliferative cells that transform them into cancer cells. Impaired DNA repair is implicated in aging and neurodegenerative disorders.  In this episode Professor Will Bohr talks about his research on the molecular mechanisms by which cells repair their nuclear and mitochondrial DNA, the involvement of impaired DNA repair in neurons in premature aging syndromes and Alzheimer’s disease, and the potential of NAD+ supplementation to sustain DNA repair and prevent neuronal degeneration. LINKS: Professor Bohr’s lab page: https://icmm.ku.dk/english/research-groups/bohr-group/ Review articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588127/pdf/cshperspectmed-AGE-a025130.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341618/pdf/nihms848291.pdf  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494058/pdf/nihms-900941.pdf

The ends of chromosomes are called telomeres. In dividing cells a reverse transcriptase called telomerase adds a six-base DNA repeat to the telomeres thereby preventing their shortening. Telomere shortening occurs in proliferative tissues during aging and has been associated with a range of diseases. This led to the dogma that the only function of telomerase is to lengthen telomeres. In this episode Professor Gabriele Saretzki and I talk about our discoveries of non-telomeric functions of the telomerase protein in neurons including effects on gene expression mitochondria, and autophagy. We also talk about the potential of drugs that increase telomerase levels for the treatment of neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. LINKS: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120688/pdf/NRR-17-2364.pdf https://onlinelibrary-wiley-com.proxy1.library.jhu.edu/doi/epdf/10.1002/jnr.1073 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938226/

Neuroscience professor Gyorgy Buzsaki discusses brain rhythms, neural syntax, and the emergence of cognition from action. He explores the synaptic basis of theta and gamma rhythms, the role of oscillations in brain communication, and the influence of sub-cortical inputs and neuromodulators on memory formation. Buzsaki also delves into the role of serotonin in REM sleep, the evolutionary perspective on brain mechanisms, and the impact of skipping breakfast on productivity and learning.

In this episode I talk with professor Thiruma Arumugam of Latrobe University about research on the effects of intermittent fasting on brain health and vulnerability to disorders such as stroke, Alzheimer’s and Parkinson’s diseases. This research was prompted by evidence that daily caloric restriction with time-restricted feeding, and every other day food deprivation can extend lifespan in rats and mice. Subsequent studies showed that intermittent fasting can protect neurons against dysfunction and damage in animal models of epilepsy, stroke, Parkinson’s disease and Alzheimer’s disease. Clinical trials then demonstrated that intermittent fasting can suppress inflammation and improve glucose regulation. Collectively, this research led to the popularization of intermittent fasting as way of improving general and cognitive health. Professor Arumugam talks about his research on intermittent fasting effects in stroke and vascular dementia models, and his ‘omics’ studies of the effects of intermittent fasting on brain neurochemistry, and the possibility that some beneficial effects of intermittent fasting can be transmitted from parents to offspring via epigenetic mechanisms. LINKS: Professor Arumugam’s webpage: https://scholars.latrobe.edu.au/tarumugam Book: https://www.amazon.com/Intermittent-Fasting-Revolution-Optimizing-Performance/dp/0262046407  Review articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039826/pdf/nihms979409.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913738/pdf/nihms958771.pdf Intermittent fasting and brain transcriptomics: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9617005/pdf/11357_2022_Article_537.pdf  

Accumulation of toxic proteins in neurons that wither and die is a fundamental problem in neurodegenerative disorders - Alzheimer’s disease, Parkinson’s disease, Frontotemporal dementia, ALS, and Huntington’s disease. In this episode Professor David Rubinsztein at the University of Cambridge talks about how impaired autophagy results in the accumulation of the toxic proteins.  Aging, and genetic and environmental factors may impair autophagy and thereby result in neurodegenerative disease. Neuroscientists and neurologists are developing ways to stimulate autophagy and thereby prevent the accumulation of toxic proteins. LINKS: Professor Rubinsztein’s lab page:  https://www.cimr.cam.ac.uk/staff/professor-david-rubinsztein-fmedsci-frs Review on autophagy in neurodegenerative disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930707/pdf/nihms-1771452.pdf Article on removing toxic proteins in neurodegenerative disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456907/pdf/nihms-1007879.pdf Impaired autophagy and amyloid accumulation in Alzheimer’s disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174056/pdf/41593_2022_Article_1084.pdf