Alzheimer's disease (AD) is thought to be caused by detrimental levels of the amyloid beta (Ab) peptide. Beta amyloid cleaving enzyme 1 (BACE1) is responsible for the first, rate limiting step in amyloid beta generation. BACE1 is elevated in the brains of AD patients, and transgenic mouse models of AD suggesting it contributes to pathogenesis. Blocking BACE1 upregulation could be therapeutically beneficial in AD, but the mechanism is not clearly understood. Brains of AD patients and people at risk of developing AD show reduced energy metabolism, and recent data indicate that impaired energy metabolism causes a translational upregulation of BACE1. Genetically preventing the phosphorylation of the translation initiation factor elF2a during energy inhibition blocks the upregulation of BACE1. Preliminary data show that Ab induced upregulation of BACE1 may also be dependent on increased elF2 a phosphorylation, so I will investigate genetic inhibition of elF2a phosphorylation can prevent BACE1 elevation in Ab treated neurons. The increase of BACE1 in response to Ab suggests a positive feedback loop may occur in AD whereby generation of Ab causes upregulation of BACE1 and even more Ab production, resulting in toxic Ab levels and eventually AD. To investigate this possibility, adeno-associated virus expressing a constitutive active form of elF2a phosphatase will be injected into the ventricles of a transgenic mouse model of AD. The constitutive active phosphatase is expected to block the increases in phosphorylated elF2a and BACE1 that are observed in this mouse model. This may be able to slow the positive feedback loop, decrease amyloid generation and deposition, and ameliorate the learning and memory deficits observed in this mouse model. The pathway of elF2a phosphorylation upstream of BACE1 upregulation may be a good target for AD therapeutics. BACE1 is the enzyme that generates amyloid beta, thought to cause Alzheimer's disease. We are investigating the upregulation of BACE1 by elF2a phosphorylation to determine if decreasing elF2a phosphorylation can prevent BACE1 elevation and ameliorate amyloid pathology and learning deficits in a transgenic mouse model of Alzheimer's disease. If so, modulation of elF2a phosphorylation may be a useful new target for Alzheimer's therapeutics.
