Mark Mattson Neuroscientist National Institute of Aging 2012 the Natures Review of Neuroscience

Mark P. Mattson PhD

Adjunct Professor of Neuroscience

mmattso2@jhmi.edu
Telephone Number: 410-937-9709

Johns Hopkins University Schoolhouse of Medicine
Section of Neurology
600 N. Wolfe Street
Baltimore, MD 21287
Meyer

Cellular and Molecular Mechanisms of Brain Aging and Neurodegenerative Disorders

A multifaceted assortment of experimental models of aging and age-related neurodegenerative disorders are existence employed in lodge to establish the molecular and biochemical changes that occur during aging and in disorders such equally Alzheimer'due south disease (AD), Parkinson's disease (PD) and stroke. Data obtained in these experimental models are integrated with data obtained in studies of both normal elderly humans and patients with neurodegenerative disorders to arrive at conclusions equally to why neuronal dysfunction and degeneration occur in the disorders. In addition to identifying the molecular and cellular alterations that lead to neuronal degeneration in historic period-related neurological disorders, investigators are elucidating the cellular signaling mechanisms that permit successful brain crumbling.

Although specific brain regions are more than severely afflicted in a given age-related neurodegenerative disorder (due east.g., hippocampus in AD and substantia nigra in PD), each disorder appears to involve similar biochemical and cellular cascades that ultimately pb to dysfunction and decease of the neurons. Specific components of such cascades include oxidative damage to proteins, lipids and DNA; metabolic compromise resulting from dumb glucose metabolism and mitochondrial dysfunction; and overactivation of glutamate receptors and disruption of neuronal calcium homeostasis. Each of these cascades is implicated in the pathogenesis of AD, PD and stroke. This laboratory has played a major role in elucidating such neurodegenerative cascades, and is currently working to accelerate our agreement of the molecular and biochemical underpinnings of age-related neurodegenerative disorders. They have shown that genetic mutations that crusade AD predispose neurons to apoptosis. Ongoing work is identifying the specific molecular triggers and executioners of neuronal apoptosis in different neurodegenerative disorders with the aim of developing drugs that interact with and cake the cell death cascade. Several different experimental models have proven valuable in elucidating cellular and molecular mechanisms, and in developing novel preventative and therapeutic strategies. Models of Advert existence employed include transgenic mice which have been engineered to express mutant genes known cause early on-onset inherited AD, models of PD include. administration of the toxin MPTP, and models of stroke include transient occlusion of the middle cognitive artery in rats and mice.

Perhaps of equal importance to knowledge of the molecular and cellular mechanisms that issue in neuronal dysfunction and death in age-related neurodegenerative disorders, is a better understanding of successful brain aging at the cellular and molecular levels. It is clear that such "anti-aging" signaling mechanisms exist because some individuals can live for more a century with very little reject in their cognitive or motor capabilities. A major goal of research in the laboratory is to place the cellular signaling mechanisms that promote the survival and plasticity of neurons during aging. They have shown that signaling pathways activated by neurotrophic factors and certain cytokines can increment resistance of neurons to degeneration in experimental models of neurodegenerative disorders. The specific molecular and biochemical changes that participate in such beneficial signaling mechanisms are currently under study.

Synapses are sites of where neurotransmission and trophic gene signaling occurs. Synaptic signaling pathways play fundamental roles in both firsthand encephalon functions such equally visual recognition and responses, and torso movements, and long-term changes such every bit learning and memory. Recent findings suggest that alterations in synaptic signaling occur very early in the course of AD and other age-related neurodegenerative disorders. The impact of oxidative stress, neurotrophic factor and cytokine signaling, and genetic aberrancies on synaptic physiology are existence examined. Piece of work is currently focussing on synaptic physiology, molecular biological science and biochemistry in experimental beast models of neurodegenerative disorders.

In studies aimed at identifying preventative and therapeutic strategies for neurodegenerative disorders, the laboratory ahs shown that rats and mice maintained on a dietary restriction (DR) regimen showroom increased resistance to degeneration of hippocampal neurons in models of Ad, increased resistance of substantia nigra dopaminergic neurons in models of PD, and increased resistance of cortical and striatal neurons in stroke models. Interestingly, DR increases neurogenesis in the hippocampus which may possibly contribute to enhanced cognitive function and resistance to injury.The cellular and molecular mechanisms that mediate the beneficial effects of DR on encephalon plasticity and resistance to injury are beingness studied.

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Source: https://neuroscience.jhu.edu/research/faculty/57

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