Presenilin in Neurodegeneration: Role of Akt/ERK Pathways

David Kang, PhD
University of California, San Diego (La Jolla, CA)
Year Awarded:
2005
Grant Duration:
April 1, 2005 to March 31, 2007
Disease:
Alzheimer's Disease
Award Amount:
$297,819
Grant Reference ID:
A2005039
Award Type:
Standard
Award Region:
US Southwestern

Presenilin in Neurodegeneration: Role of Akt/ERK Pathways

Details

Inherited mutations in two similar genes, presenilin 1 (PS1) and presenilin 2 (PS2), cause the most aggressive forms of AD with disease onset between 30 to 60 years of age. It is widely believed that these genes cause AD by accelerating amyloid plaque deposition in the brain. Growing evidence has found that presenilin dysfunctions may also drive tangle pathology independent of the effects from amyloid plaques. This finding is significant, because many therapeutic agents currently under development are designed to reduce amyloid plaques by inhibiting the functions of both PS1 and PS2. These agents may end up inadvertently promoting nerve damage and tangle formation instead. It is important to understand whether mutations in PS1 or PS2 can influence nerve damage and tangle formation independent of the effects associated with amyloid plaques. Experimental data has indicated that 2 molecular pathways (Akt and ERK) important for nerve cell survival are severely compromised in cells lacking both PS1 and PS2. Dr. Kang plans on testing whether delivery of activated Akt or ERK genes can prevent brain damage.

Publications

Repetto, E., Yoon, I.S., Zheng, H. and Kang, D.E. (2007) Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway. J Biol Chem. 282(43):31504-31516.  

Kang, D.E., Yoon, I.S., Repetto, E., Busse, T., Yermian, N., Ie, L., Koo, E.H. (2005) Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. J Biol Chem. 280(36):31537-31547. [Alzforum Recommended Paper]  

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