Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

Abstract

Abstract. The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESE-NILIN (PSEN) proteins is in ␥-secretase enzyme activity. One substrate of ␥-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A␤PP/APP) that is a fAD mutation locus. A␤PP is the source of the amyloid-␤ (A␤) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on ␥-secretase activity and A␤ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on ␥-secretase in AD. We then discuss the main ideas regarding the role of ␥-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and A␤PP) and look at alternative roles for A␤PP and A␤ in fAD. We present a case for an alternative interpretation of published data on the role of ␥-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN

Transcriptome analysis indicates dominant effects on ribosome and mitochondrial function of a premature termination codon mutation in the zebrafish genepsen2

“…In a 2016 review, we suggested that mutant PRESENILIN holoproteins may interfere with normal holoprotein (putative) multimerization and, thereby, act in a dominant negative manner to interfere with the holoproteins’ normal activity in promoting this N-glycosylation event. (We suggested that the involvement of PRESENILIN holoproteins in multimerization may explain the “reading frame preservation” rule that states that all EOfAD mutations in the PSEN genes must preserve an open reading frame that uses the original stop codon (12). ) Curiously, both of the PRESENILIN activities mentioned above, the regulation of MAM formation and of endolysosomal acidification, appear to be mediated by the C99 fragment (β-CTF) of APP (57, 60) and this implies that these activities of the PRESENILINs may share a common molecular mechanism.…”

Amyloid precursor protein and endosomal‐lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease

“…Less often considered to be another outcome of γ‐secretase loss of function in PSEN1 fAD is the substantial and consistent elevated level of APP–βCTF (162, 163), which accumulates in lysosomes and disrupts their functions. In addition, both presenilins have secretase‐independent roles as uncleaved polypeptides (119, 142, 164, 165).…”

Genome-Wide Association Studies Associated with Backfat Thickness in Landrace and Yorkshire Pigs

“…NIHL is a commonly recorded disorder, accounting for 7% to 21% of hearing loss [ 9 ]. NGFR is the nerve growth factor receptor [ 10 ] and dystrobrevin-binding protein 1 ( DTNBP1 ) is an NMDA-receptor mediated signaling gene. NMDA is N-methyl-D-aspartate and DTNBP1 has the ability to modulate synaptic plasticity and glutamatergic transmission through NMDA receptors [ 11 ].…”