Molecular and physiological processes relevant to pathogenesis in Alzheimer's disease.
Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by progressive impairments in memory and cognitive function that occurs in the elderly. As life expectancies have increased in the industrial world, it is estimated that more than 10 million Americans will have AD by 2050. Neuropathologically, a highly selective but massive neuronal loss takes place in the limbic areas that play a significant role in memory function, such as the hippocampal formation, presubiculum and entorhinal cortex. Two characteristic lesions are formed in the affected brain areas. These are intracellular neurofibrillary tangles and extracellular deposits of ß-amyloid (Aß ), a 4 kDa peptide derived from a larger amyloid precursor protein (APP). Three genes have been identified that mutated in pedigrees with early-onset forms of AD (FAD). These genes encode presenilin 1 (PS1), presenilin 2 (PS2) and APP. Expression of these mutant proteins results in the increased production and fibrillogenic properties of Aß, and its subsequent deposition. It is well established that PS play a major role in the gamma-secretase activity that cleaves APP to yield Aß. Research in my lab focuses on understanding molecular and physiological processes relevant to pathogenesis of AD. In particular, we investigate the physiological roles of APP and PS and ask how mutant forms of these proteins lead to misregulation of fundamental physiological processes and induce AD. Our investigations have revealed that in addition to a major role in the gamma-secretase enzymatic activity that cleaves APP and other membrane proteins, PS1 plays a critical role in multiple pathways in neurons. Thus, for example, we have demonstrated that PS1 plays a role in neuronal survival in the entorhinal cortex of transgenic mice, regulates proliferation of progenitor cells and neurogenesis in the dentate gyrus of the adult brain, and regulates trafficking and anterograde axonal transport of selected membrane proteins including APP. In that regard, our recent exciting studies show that environmental factors in concert with genetic factors play a role in regulation of these processes. Using a variety of molecular and cellular approaches as well as transgenic animal models harboring FAD-linked variants, our investigations are aimed at clarifying the normal and pathological mechanisms underlying these fundamental processes in neurons. For example, we ask how mutations in APP and PS affect severely and selectively specific neuronal lamina in the brain; what is the mechanism underlying AD-associated misregulation of neurogenesis in the dentate gyrus, and its implications on the progression of pathology; and how the cross talk between genetic and environmental factors modulate the development of AD. We anticipate that our investigations will lead to the development of therapeutic strategies to prevent or ameliorate the clinical and pathological manifestations of AD.
Selected References
Lazarov O, Peterson LD, Peterson DA, Sisodia SS (2006) Expression of a FAD-linked PS1variant enhances perforant pathway lesion-induced neuronal loss in the entorhinal cortex. J Neurosci 26(2):429-434.
Lazarov O, Robinson J, Tang YP, Hairston I, Korade-Mirnics Z, Lee VM, Hersh LB, Sapolsky RM, Mirnics K, Sisodia SS (2005) Environmental Enrichment Reduces Aß Levels and Amyloid Deposition in Transgenic Mice. Cell 120:701-713.
Lazarov O, Morfini G, Lee EB, Farah MH, Szodorai A, DeBoer S, Koliatsos VE, Kins S, Lee VM, Wong, PC, Price DL, Brady ST, Sisodia SS (2005) Axonal Transport, Amyloid Precursor Protein, Kinesin-1 and the processing apparatus: Revisited. J. Neurosci. 25(9):2386-2395.
Lazarov O, Lee M, Peterson DA, Sisodia SS (2002) Evidence that synaptically released ß-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J. Neurosci. 22(22):9785-9793.
