Robert Vassar

Robert Vassar, PhD
Associate Professor
Cell and Molecular Biology

Molecular Mechanisms of Alzheimer's Disease

E-mail:   
r-vassar@northwestern.edu

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. The degeneration of neurons in regions of the brain important for cognition results in progressive dementia that slowly robs AD patients of their memories, personalities, and eventually their lives. No therapies currently exist that treat the underlying cause of AD, and if none are found, the number of AD patients will rise dramatically as the population ages. Clearly, the need for an effective AD therapy is great, and understanding the pathophysiological mechanisms that underlie neurodegenerative processes in AD is essential for the rational design of AD drugs.

AD pathology is defined 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 correlated with autosomal dominant forms of familial AD, suggesting that Ab42 has a critical and early role in AD pathogenesis. Ab is derived from the amyloid precursor protein (APP) via endoproteolysis by two proteases called the b- and g-secretases. The b-secretase, a novel aspartic protease named 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, which have been instrumental in validating 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 toxic side effects. Although BACE1 is clearly a key enzyme required for the processing of APP into Ab, other potential substrates and functions of BACE1 may also exist and are under investigation in our lab.

Our ongoing research focuses on the role of Ab and BACE1 in normal biological processes and in disease mechanisms related to AD. We are particularly interested in the functions of BACE1 and the homologue, BACE2, and regulation of Ab production by BACE1. 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 during brain aging that may promote neurodegeneration.

Publications:
Yan, Q., Zhang, J., Liu, H., Babu-Khan, S., Vassar, R., Biere, A., Citron, M., and Landreth, G. (in press). Anti-inflammatory drug therapy alters b-amyloid processing and deposition in an animal model of Alzheimer’s disease. J. Neurosci.

Luo, Y., Bolon, B., Damore, M.A., Fitzpatrick, D., Liu, H., Zhang, J., Yan, Q., Vassar, R., and Citron, M. (in press). BACE1 (b-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol. Dis.

Estus, S., Borchelt D., Kindy, M.S., Vassar, R. (2002). Ab deposition is essential to AD neuropathology. J. Alzheimer’s Dis. 4, 133-138.

Vassar, R. (2001). The b-secretase, BACE: a prime drug target for Alzheimer’s disease. J. Mol. Neurosci. 17, 157-169.

Luo, Y., et al. (2001). Mice deficient in BACE1, the Alzheimer’s b-secretase, have normal phenotype and abolished b-amyloid generation. Nature Neurosci. 4, 231-232.

Vassar, R., and Citron, M. (2000). Ab generating enzymes: recent advances in b- and g-secretase research. Neuron 27, 419-422.

Bennett, B.D., et al. (2000). A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s b-secretase. J. Biol. Chem. 275: 37712-37717.

Haniu, M., et al. (2000). Characterization of Alzheimer’s b-secretase protein BACE: a pepsin family member with unusual properties. J. Biol. Chem. 275, 21099-21106.

Bennett, B.D., et al. (2000). Expression analysis of BACE2 in brain and peripheral tissues. J. Biol. Chem. 275, 20647-20651.

Vassar, R., et al. (1999). b-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735-741.


Pub med

View Publications by Bob Vassar listed in the National Library of Medicine (PubMed).