How APP Intracellular Domain (AICD) contributes to Alzheimer’s disease?
The cause of Alzheimer's disease (AD) is not conclusively known and there is no cure for or effective treatment against the disease. Amyloid precursor protein (APP) plays a key role in AD pathogenesis and its processing generates many peptides including amyloid-beta (Ab), which is widely believed to be the primary cause of AD. However, there is growing evidence that non-amyloid mechanisms also contribute to AD pathogenesis.
Proteolytic processing of APP that generates Ab peptides also releases free APP Intracellular domain (AICD) into the cytoplasm. We and others previously showed that AICD can induce many deleterious events including altered cell signaling, gene expression and cell death. We recently showed that AICD transgenic mice recapitulate major AD-like features such as hyperphosphorylation and aggregation of tau, impaired electrical activity and seizures, memory deficits and neurodegeneration. We also observed increased levels of AICD in AD brains. Together, these findings indicate that AICD, in addition to Ab, can contribute to AD pathologies (Figure 1).
Currently, we are elucidating the mechanism that underlies the deleterious effects of AICD. Our preliminary data shows that AICD activates multiple kinases and alters downstream signaling pathways. We are using neuronal and non-neuronal tissue culture cells to identify various steps in the pathway and identify the cellular components. Over the long term, we plan to use this information to identify new drugs or drug targets that will be effective against AD.
To understand APP function in vivo using a zebrafish model system
Although APP has been studied extensively, its precise functional role in vivo is not well understood. In vitro studies have suggested a role for APP in cell migration and axonal elongation. However, APP knock out mice show only subtle phenotypic changes (probably because of the presence of two closely related proteins) making it difficult ascertain APP function in vivo.
To overcome this problem, we are studying APP function in zebrafish model organism. Zebrafish offers many advantages to study protein functions during development. We previously showed that downregulation of APP (by injecting APP morpholino) results in convergence-extension defects. Such developmental defects are consistent with the in vitro data suggesting APP involvement in cell migration. However, our in vivo studies extend those observations and also implicate APP in signal transduction pathways. We are currently characterizing these signaling events and exploring the possibility that alterations in these signaling events may also form a basis of AD pathology.
In addition, we are using GFP-transgenic fish to study the movement of individual neurons during embryonic development. Our studies show that loss of APP function impairs migration of motor neurons and inhibits axonal growth (Figure 2). We are now examining whether familial AD mutations in APP have differential effects on neuronal migration and axonal elongation. These studies could shed light on how mutations in APP affect its function during development and whether this plays any role in the development of AD pathology.
