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Hemant K. Paudel

Hemant K. Paudel, PhD

Molecular & Regenerative Medicine

Alzheimer’s disease, Amyloid beta peptide, Apo lipoprotein -(ApoJ), Beta Secretase, Clusterin, Clusterin mRNA splicing, Early growth response-1, Neurofibrillary Tangles, Synaptic loss, Tau Protein
  • Senior Investigator, Lady Davis Institute for Medical Research
  • Associate Professor, Department of Neurology and Neurosurgery, McGill University

Contact details

(514) 340-8222 ext. 24866
hemant.paudel@mcgill.ca

Snapshot

Alzheimer’s disease (AD) is the most common form of dementia in the elderly population. The main pathological features of AD are progressive loss of nerve cells and deposition of abnormal protein aggregates called senile plaques (SP) and neurofibrillary tangles (NFTs). Studies in animal and cell models have shown that both plaques and tangles cause nerve damage leading to loss of cognitive functions. The main focus of Professor Paudel’s laboratory is to elucidate the molecular mechanisms by which SPs and NFTs are formed and how these two protein aggregates cause neurodegeneration leading to cognitive loss. There is no effective treatment for AD. Our long-term goal is to identify therapeutic molecular targets for treatment of AD.

Important Links :

See Hemant K. Paudel's publications on PubMed

Major Research Activities

Hemant K. Paudel’s research focuses on the following:

  • NFTs contain tau protein. In normal brain tau protein regulates microtubule structure. In AD brain tau becomes hyperphosphoprylated (contains more phosphate than in normal brain) and aggregates forming NFTs. One of the major area of our research is to characterize biochemical pathway involved in the hyperphosphorylation of tau protein in normal brain and to determine how this pathway is overactivated in AD brain.
  • Identify and characterize molecular pathways that regulate the level of amyloid beta protein in the normal and AD brains.
  • Investigate molecular mechanisms by which hyperphosphorylated tau and amyloid beta protein cause nerve damage leading to loss of cognitive function.

The specific research areas in the laboratory include:

  • Tau protein is phosphorylated by a number of kinases in the brain. Cyclin-dependent protein kinase 5 (Cdk5) has been demonstrated to be overactivated in AD brain. We have elucidated the molecular pathway that drives Cdk5 activation in the brain. This pathway is one of the major projects in our lab.
  • Amyloid beta peptide, the main component of SP, is formed by a sequential cleavage of amyloid precursor protein (APP) by beta secretase followed by gamma secretase. Beta secretase is over activated in the AD. Our laboratory has identified a transcription factor that regulates beta secretase level in neurons. How this transcription factor drives beta secretase activity leading to accumulation of excess amyloid beta peptide in AD is being studied in our lab.
  • Clusterin (apo-J) is one of the major risk factors for late-onset form of AD. There are two isoforms of clusterin, a secretory form and a nuclear form. Theses isoforms are products of alternative splicing of clusterin mRNAs. The secretory form is neuroprotective. The nuclear form on the other hand is neurotoxic and promotes apoptosis. In normal brain, the levels of secretory form and nuclear form are balanced. However, in AD the mechanism that maintains the levels of these two isoforms is lost leading to excess.

Recent Publications and References