Robert Vassar, PhD

  • Professor, Neurology; Feinberg School of Medicine
  • Cell Biology, Neurobiology of Disease
  • Interdepartmental Neuroscience

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. The progressive degeneration of neurons in regions of the brain important for cognition causes the dementia that slowly robs AD patients of their memories, personalities, and eventually their lives. No therapies currently exist that treat the underlying pathology of AD, and if none are found, the number of AD patients is projected to rise dramatically due to the aging of the population. Clearly, the need for AD treatments is great, and understanding the pathophysiological mechanisms that underlie neurodegeneration in AD is essential for rational design of therapies.

AD pathology is characterized by two microscopic brain lesions, amyloid plaques and neurofibrillary tangles. Amyloid plaques are extracellular deposits of the beta-amyloid peptide (Ab), and the longer 42 amino acid form, Ab42, is strongly associated with autosomal dominant forms of familial AD suggesting that Ab42 has a critical and early role in AD pathogenesis. Ab is generated from the amyloid precursor protein (APP) by endoproteolysis from two proteases called the b- and g-secretases. The b-secretase, a novel aspartic protease termed BACE1, was initially cloned and characterized by our group (Vassar, et al., 1999). BACE1 is required for the generation of all forms of Ab, including Ab42, and therefore is a prime drug target for the treatment of AD. We have recently generated BACE1 knockout mice by gene targeting and have validated BACE1 as the authentic b-secretase in vivo (Luo et al., 2001). Importantly, BACE1 knockout mice have a normal phenotype, suggesting that therapeutic inhibition of BACE1 for AD may be free of mechanism-based toxicity. Although BACE1 is clearly a key enzyme required for the processing of APP into Ab, other potential substrates and functions of BACE1 are unknown.

Our ongoing research focuses on the role of Ab and BACE1 in normal biological processes and in disease mechanisms of relevance to AD. We are particularly interested in the functions of BACE1 and the homologue, BACE2, and the cell biology of Ab in neurons. Cellular and molecular studies of BACE1 and BACE2 knockout mice will be important for elucidating the biological functions of these novel aspartic proteases and identifying their substrates. Finally, we are interested in the role of inflammation in AD pathophysiology, novel transgenic and knockout mouse models of AD, and molecular changes that may occur during brain aging leading to neurodegeneration.