Veronica Galvan, Ph.D.
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Alzheimer’s disease (AD) is an incapacitating age-related neurodegenerative disorder characterized by memory loss and progressive deterioration of cognitive function. AD and AD-related dementia accounts for more than 60% of all dementia cases. Current treatment options for AD are limited, and only temporarily palliative. Because of its high prevalence and the continuing increase of the aged population, AD is a major health problem with serious negative consequences for affected individuals and their families, as well as local and worldwide economies.
Our research is focused on the identification of molecular and biochemical alterations that cause AD. By understanding how AD is triggered and how it develops, we can devise ways to slow or prevent the disease. We use genetic manipulations in mouse models, behavioral, immunohistochemical and biochemical approaches, in vivo brain optical and functional imaging, in vivo brain blood flow measures, and cellular and molecular biology tools to understand the initiating molecular events in AD, determine the effects of potential drug candidate molecules, and define the mechanisms involved.
Amyloid-ß regulation. Late stage AD is characterized by brain lesions that include amyloid plaques enriched in amyloid-beta (Aß) and neurofibrillary tangles containing misfolded forms of the microtubule-binding protein tau. Understanding the mechanisms by which Aß and tau are dysregulated and become pathogenic is needed to formulate strategies to prevent or treat AD. Using surrogate models of AD, we have identified a key role of the mammalian target of rapamycin (TOR), a major regulator of metabolism and organismal aging, in the control of brain Aß levels through the modulation of autophagy.
Reduced cerebral blood flow and blood-brain barrier breakdown in AD: The earliest stages of AD are marked by decreased cerebral blood flow and blood-brain barrier (BBB) breakdown. Understanding the causes for diminished cerebral blood flow and BBB collapse in AD will allow us to devise methods to slow or block progression of the disease at its earliest stage. We recently identified TOR-dependent mechanisms that drive the decrease in brain blood flow in AD models through the inhibition of endothelial nitric oxide synthase (eNOS) and the collapse of BBB through downregulation of the key tight junction scaffold protein junctional adhesion protein A (JAM-A). Our studies show that preservation of endothelium-dependent vasodilation is required for the restoration of cerebral blood flow in models of AD, and that the resulting increase in brain circulation enables the continuous elimination of Aß from brain. mTOR is thus involved in the control of net Aß levels through autophagy in neurons, and in the regulation of clearance of Aß from brain through the cerebral vasculature. Drugs that attenuate mTOR thus establish a feedforward loop that reduces net Aß levels in brain by simultaneously reducing its production and increasing its elimination from brain.
Microvascular tau in AD and other tauopathies: We recently showed that prefilamentous aggregates of hyper-phosphorylated tau (tau oligomers) accumulate in brain microvessels of AD and of progressive supranuclear palsy (PSP) patients, suggesting that, like Aß, extracellular tau may propagate to non-neuronal cell types and thus contribute to brain microvascular dysfunction in AD and other neurodegenerations associated with tauopathy. We are currently exploring the co-occurrence of misfolded tau and Aß in cerebrovasculature of AD and PSP, and the propagation of misfolded tau oligomers to non-neuronal cell types in AD brain.
So far, our research has led us to discover a key role of TOR in the initiation of neuronal and brain vascular dysfunction in AD through pathways involving Aß and tau. Because TOR controls key aspects of metabolism in most cell types we hypothesize that TOR may be involved in several cell-specific complex disease mechanisms driving neurodegeneration in AD. Thus, to define the role of TOR in AD, we study mechanisms by which pathways centered on TOR but mediating distinct processes in different brain compartments such as neurons and brain vascular cells synergize to precipitate loss of function. Based on our findings, we are currently engaged in safety studies of rapamycin, and in drug screening/drug discovery efforts in a search for (a) compounds that regulate the activity of the TOR pathway and (b) compounds that regulate JAM-A levels, that may be used to slow or treat AD and potentially other dementias.
Candice Van Skike
Cerebral Microvascular Accumulation of Tau Oligomers in Alzheimer's Disease and Related Tauopathies.
mTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment.
Vascular mTOR-dependent mechanisms linking the control of aging to Alzheimer's disease.