Henry Querfurth, MD PhDEdit My Page
Alzheimer's Disease is multifactorial and many biochemical pathways are deranged. A major challenge is to determine their temporal sequence, relative importance, and which are causative, secondary or self repairing. The end result, neuron and synapse loss and accumulation of damaged proteins (amyloids), will require concurrent therapies to arrest or reverse. We explore various targets of amyloid damage, e.g. energy production, protein clearance mechanisms, signaling pathways, calcium regulation and the replication machinery. Several of these are specific enough to have drug discovery potential.
Dr Querfurth received his M.D. and Ph.D.in neuroscience at U. of Rochester, NY. Thereafter, he completed residencies in Internal Medicine and Neurology at U. of Washington, Seattle. Next, he completed a clinical and basic research fellowship in memory disorders at the Brigham and Women's Hospital, HMS, Boston. Since then, Dr. Querfuth has pursued independent research in Alzheimer's disease and a related condition, Inclusion Body Myositis, first within the Tufts University School of Medicine and now at Brown University. He is also developing a technology to non-invasively measure intracranial pressure. He co-directs the Memory clinic at Rhode Island Hospital and divides his time between clinical practice in cogntive and general Neurology, basic and translational research and clinical trial investigations.
Alzheimer's Disease (AD) and Inclusion Body Myositis pathogenesis.
The theme of our lab is that intracellular accumulations of misfolded proteins are cytotoxic to specialized cell types due to selective vulnerabilities of certain steps within key signaling, metabolic, cycle control and homeostatic pathways. To model the contribution of intracellular amyloid molecules to the early pathogenesis of Alzheimer disease, we culture primary neurons from control and transgenic mice brain or use transfected neuronal cell lines. Normal and mutated forms of bAPP, b-amyloid and/or tau proteins, central to AD pathogenesis, are then expressed either genetically or from inducible adenovirus and Herpes-based constructs.
We are actively investigating three essential homeostatic mechanisms: 1) the proteasome degradation machinery, 2) the insulin-responsive, PI3K/Akt signaling pathway and 3) mitochondrial metabolism. Manipulations of these paths in cultured cells involve the co-expression of putative 'protective' genes encoded by lentiviruses, generated here or obtained through collaboration. The specific targets we uncover are checked against brain specimens from AD patients. An in vitro-based assay for the insulin pathway target is being set up for use in a high-throughput drug screen. Future studies are planned to further investigate the utility of various heat shock proteins to protect mitochondrial components from AD damage and to explore expression regulation of amyloid transport receptors.
Parallel experiments model another human disorder in which the same Ab and phosphorylated tau molecules are implicated, Inclusion Body Myositis. IBM is a common but incurable muscle disease of the aged which has quasi-degenerative and inflammatory features. Interestingly, b-amyloid accumulates inside IBM skeletal muscle fibers, in contrast to AD where extracellular plaques and soluble species of amyloid are the major focus. We culture primary myotubes from a transgenic mouse for this disorder created here. The targets identified in the neuronal experiments above are re-tested using live muscle cells and frozen biopsy samples from patients.
A potential treatment for IBM could come from finding target(s)of amyloid that are common to both neurons and skeletal muscle. Since a blood-brain barrier is not present in this disorder, drug delivery may be facilitated. Future studies will examine a protein degradation pathway related to FOXO signaling in IBM-like skeletal muscle and whether aberrant cell cycle re-entry is a significant factor in disease pathogenesis. We plan to create an upgraded animal model.
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