Johns Hopkins School of Medicine

Cellular and Molecular Mechanisms of Brain Aging and Neurodegenerative Disorders

A multifaceted array of experimental models of aging and age-related neurodegenerative disorders are being employed in order to establish the molecular and biochemical changes that occur during aging and in disorders such as Alzheimer's 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 as 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 age-related neurological disorders, investigators are elucidating the cellular signaling mechanisms that allow successful brain aging.

Although specific brain regions are more severely affected in a given age-related neurodegenerative disorder (e.g., hippocampus in AD and substantia nigra in PD), each disorder appears to involve similar biochemical and cellular cascades that ultimately lead to dysfunction and death of the neurons. Specific components of such cascades include oxidative damage to proteins, lipids and DNA; metabolic compromise resulting from impaired 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 advance our understanding of the molecular and biochemical underpinnings of age-related neurodegenerative disorders. They have shown that genetic mutations that cause 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 block 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 AD being employed include transgenic mice which have been engineered to express mutant genes known cause early-onset inherited AD, models of PD include. administration of the toxin MPTP, and models of stroke include transient occlusion of the middle cerebral artery in rats and mice.

Perhaps of equal importance to knowledge of the molecular and cellular mechanisms that result 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 than a century with very little decline in their cognitive or motor capabilities. A major goal of research in the laboratory is to identify 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 increase 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 factor signaling occurs. Synaptic signaling pathways play fundamental roles in both immediate brain functions such as visual recognition and responses, and body movements, and long-term changes such as 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 being examined. Work is currently focussing on synaptic physiology, molecular biology and biochemistry in experimental animal 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 exhibit 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 brain plasticity and resistance to injury are being studied.