Presenilin 1 Regulates Membrane Homeostatic Pathways that are Dysregulated in Alzheimer's Disease

Mutations in the PSEN1 gene, encoding presenilin 1 (PS1), are the most common cause of familial Alzheimer's disease (fAD). Since the first mutations in the PSEN1 gene were discovered more than 25 years ago, many postulated functions of PS1 have been investigated. The majority of earlier studies focused on its role as the catalytic component of the γ-secretase complex, which in concert with β site amyloid precursor protein cleaving enzyme 1 (BACE1), mediates the formation of Aβ from amyloid-β protein precursor (AβPP). Though mutant PS1 was originally considered to cause AD by promoting Aβ pathology through its protease function, it is now becoming clear that PS1 is a multifunctional protein involved in regulating membrane dynamics and protein trafficking. Therefore, through loss of these abilities, mutant PS1 has the potential to impair numerous cellular functions such as calcium flux, organization of proteins in different compartments, and protein turnover via vacuolar metabolism. Impaired calcium signaling, vacuolar dysfunction, mitochondrial dysfunction, and increased ER stress, among other related membrane-dependent disturbances, have been considered critical to the development and progression of AD. Given that PS1 plays a key regulatory role in all these processes, this review will describe the role of PS1 in different cellular compartments and provide an integrated view of how PS1 dysregulation (due to mutations or other causes) could result in impairment of various cellular processes and result in a "multi-hit", integrated pathological outcome that could contribute to the etiology of AD.