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Chemical Neuropathology Laboratory

07/17/12

Khalid Iqbal, PhD, Head

khalid.iqbal@opwdd.ny.gov

The Chemical Neuropathology Laboratory studies the molecular mechanisms of neurofibrillary degeneration and of regeneration of the brain by identifying protein phosphatases and kinases that regulate the phosphorylation of tau and regulation of these enzymes, the identification of various subgroups of Alzheimer disease on the basis of cerebrospinal fluid levels of specific disease markers, the trophic factors involved in the promotion of the dentate gyrus neurogenesis and the differentiation of the neural progenitor cells in mature neurons. These studies involve the identification and validation of therapeutic targets; the development of high-throughput screening assays and of model therapeutic lead compounds; and the identification and validation of molecular markers as outcome measures with which the efficacy of the therapeutic drugs can be measured. Our basic research on understanding the molecular mechanisms of neurofibrillary degeneration and of the regeneration of the brain and the development of model therapeutic drugs based on these mechanisms will benefit patients with Down syndrome, Alzheimer disease and related disorders.

We discovered that neurofibrillary tangles, which are a hallmark of Alzheimer disease, adults with Down syndrome, frontolobar dementias and other tauopathies, are made up of abnormally hyperphosphorylated tau protein. Hyperphosphorylation of tau leads to cognitive impairment and thus is a major focus of research worldwide. Inhibition and prevention of hyperphosphorylation of tau is a major goal in the field. We have developed monoclonal antibodies to the amino-terminal projection domain of tau and have demonstrated for the first time that passive immunotherapy with these antibodies can rescue cognitive impairment and both tau and Abeta pathologies—the two histopathological hallmarks of Alzheimer disease, adults with Down syndrome and other tauopathies, in preclinical studies. We have developed small neurogenic/ neurotrophic peptides that enhance learning and memory in normal adult mice. Employing our lead peptideric compound, we have discovered that initiation of the treatment in utero can prevent both developmental delay and, then in adult life, cognitive impairment in the trisomic mouse model Ts65DN of Down syndrome. We have also found that our compound can rescue autism-like behavioral impairment, which we induced by injecting sera from children with autism in the brains of newborn rat pups. Currently, we are testing these lead therapeutic compounds in transgenic mouse models of Alzheimer-like neurodegeneration and related conditions.  We have licensed our compound and antibodies to a biotech company for further drug development for human use.