Mutations in presenilin 2 and its implications in Alzheimer's disease and other dementia-associated disorders

Abstract

Alzheimer's disease (AD) is the most common form of dementia. Mutations in the genes encoding presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein have been identified as the main genetic causes of familial AD. To date, more than 200 mutations have been described worldwide in PSEN1, which is highly homologous with PSEN2, while mutations in PSEN2 have been rarely reported. We performed a systematic review of studies describing the mutations identified in PSEN2. Most PSEN2 mutations were detected in European and in African populations. Only two were found in Korean populations. Interestingly, PSEN2 mutations appeared not only in AD patients but also in patients with other disorders, including frontotemporal dementia, dementia with Lewy bodies, breast cancer, dilated cardiomyopathy, and Parkinson's disease with dementia. Here, we have summarized the PSEN2 mutations and the potential implications of these mutations in dementia-associated disorders.

Keywords: Alzheimer’s disease; mutations in presenilin 2.

Figure 1

The process of Aβ aggregation. Notes: Amyloid precursor protein (APP) is a transmembrane protein. APP processing includes non-amyloidogenic and amyloidogenic pathways. Non-amyloidogenic pathway (left): APP is cleaved by α-secretase in the middle of Aβ with production soluble APPα (sAPPα) and C-terminal fragment α (CTFα). Then CTFα is hydrolyzed by γ-secretase to generate APP intracellular domain (AICD). Amyloidogenic pathway (right): APP is cleaved by β-secretase resulting in N-terminal soluble APPβ (sAPPβ) leaving the C-terminal fragment β (CTFβ) which is hydrolyzed by γ-secretase to yield Aβ and AICD. Presenilin, nicastrin, anterior pharynx-defective 1 (APH-1) and presenilin enhancer 2 (PEN-2) are the parts of γ-secretase. PSEN mutation might increase γ-secretase activity to cause plaque forming. Abbreviations: AICD, APP intracellular domain; APP, amyloid precursor protein; APH-1, anterior pharynx-defective 1; CTFα, C-terminal fragment α; CTFβ, C-terminal fragment β; sAPP, soluble APP; PEN-2, presenilin enhancer 2.

Figure 2

Missense mutations in PSEN2 and their pathogenicity. Abbreviations: SNP, single nucleotide polymorphism; EX, exon.