New Insights Regarding the Intracellular Effects, Trafficking, and Quality Control of the Amyloid Precursor Protein: Implications for Alzheimer’s Disease Pathogenesis


Journal Title

Journal ISSN

Volume Title



Alzheimer’s disease (AD) is the most common form of age-related dementia. Our current understanding of AD pathogenesis is largely based on data from cases of relatively rare early-onset forms of the disease, collectively known as familial AD (FAD). FAD is associated with discrete mutations in three genes: PSEN1 and PSEN2, which encode the presenilin proteins, and APP, which encodes the amyloid precursor protein (APP). Several hypotheses exist for the pathogenesis of AD. According to the amyloid cascade hypothesis, AD pathogenesis is associated with a series of molecular events which leads to the aggregation and deposition of specific proteolytic fragments of APP. There is also evidence that disruption of intracellular calcium homeostasis contributes to AD pathogenesis, especially in cases of FAD related to PSEN mutations. However, important questions remain unanswered regarding the pathogenesis of AD, and thus, research has increasingly focused on identifying new genetic associations with late-onset AD with the hope that they will shed some light on disease mechanisms. Recently, the gene encoding ubiquilin was shown to be associated with late-onset AD, but the molecular mechanism by which the ubiquilin protein contributes to disease pathogenesis is still unclear. We sought to determine: 1) whether disruption of intracellular calcium homeostasis is a common causal factor in all forms of FAD, and 2) the mechanisms by which the ubiquilin protein contributes to the pathogenesis of late-onset AD. Using calcium imaging techniques, we show that FAD-linked mutations in APP do not directly perturb intracellular calcium homeostasis, suggesting that disruption of calcium is not an initiating event in the development of all forms of AD. Using biochemical and cellular approaches, we determined that ubiquilin directly interacts with APP and regulates its trafficking and proteolytic processing. Furthermore, we show that ubiquilin possesses molecular chaperone activity and prevents the aggregation of APP. Examination of post-mortem brain tissue from AD revealed decreased ubiquilin protein levels, suggesting that the pathogenesis of late-onset AD is related to alterations in APP trafficking and quality control. Our results point to the restoration of ubiquilin protein level and/or function as therapeutic targets for AD.



Alzheimer's, neurodegeneration, calcium, chaperone, trafficking