X11 Proteins Regulate the Translocation of Amyloid β-Protein Precursor (APP) into Detergent-resistant Membrane and Suppress the Amyloidogenic Cleavage of APP by β-Site-cleaving Enzyme in Brain

Abstract

X11 and X11-like proteins (X11L) are neuronal adaptor proteins whose association to the cytoplasmic domain of amyloid ␤-protein precursor (APP) suppresses the generation of amyloid ␤-protein (A␤) implicated in Alzheimer disease pathogenesis. The amyloidogenic, but not amyloidolytic, metabolism of APP was selectively increased in the brain of mutant mice lacking X11L (Sano, Y., Syuzo-Takabatake, A., Nakaya, T., Saito, Y., Tomita, S., Itohara, S., and Suzuki, T. APP3 is a type I membrane protein and is the precursor of amyloid ␤-protein (A␤), which is the principal component of senile plaques, a pathological hallmark in the Alzheimer disease (AD) brain. The production, aggregation, and deposition of A␤ are widely believed to be central to the pathogenesis in AD (reviewed in Ref. 1). APP is subjected to two types of cleavage in both a potentially amyloidogenic pathway and an amyloidolytic (or nonamyloiodgenic) pathway. Amyloidogenic cleavage of APP is mediated by ␤-site APP-cleaving enzyme (␤-secretase or BACE), which generates the C-terminal fragment CTF␤, which contains an intact A␤ sequence, whereas amyloidolytic cleavage of APP is mediated by one of several ␣-site APP-cleaving enzymes (␣-secretases, including ADAM10 and ADAM17), thereby generating CTF␣, which contains only the C-terminal half of A␤ peptide (reviewed in Refs. 1 and 2). These CTFs are further cleaved within the transmembrane domain by the ␥-secretase aspartyl protease complex composed of presenilin (PS), nicastrin, Aph-1, and Pen-2. The ␥-secretase cleavage generates A␤ and the APP intracellular domain from CTF␤ and, alternatively, ␥-secretase generates p3 peptide and APP intracellular domain from CTF␣ (reviewed in Refs. 3 and 4). However, it is still unclear exact where along the intracellular trafficking itinerary of APP each of these cleavages occurs. The molecular mechanisms regulating secretase reactions are also poorly understood (reviewed in Ref. 5). Recent growing evidence suggests that APP processing by BACE occurs in cholesterol-and sphingolipid-rich detergent-resistant membrane domains (DRM domains) also known as lipid rafts (6 -9). DRM are suggested to be the principal compartments containing intracellular monomeric and oligomeric A␤ in brain (10, 11). The ␥-secretase complex also associates with DRM and is especially active there (12-15), indicating that A␤ may be largely the product of a series of intra-DRM reactions.X11 proteins (X11s) comprise a family of three evolutionarily conserved molecules: 1) X11/X11␣/Mint1; 2) X11-like (X11L)/

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

“…These results, although apparently at odds with those described above, might be attributable to the different genetic backgrounds used in the different studies: the studies described above examined endogenous APP and A peptides in the brains of knock-out mice [72,73]. The studies conducted by Ho et al examined human A peptides in double-transgenic mice in which human mutant APP and mutant -secretase presenilin1…”

“…Thus, the precise role of X11 proteins in the regulation of APP processing in human brain remains unknown; however, it is likely that these proteins play a critical role. Among the X11 proteins, X11L is likely to be the most important regulator for the processing of APP in brain because mice with defective X11L display the most striking changes in APP processing compared to other members of the X11 family [73,74]. This might be a result of the higher affinity of X11L for APP or the broader distribution of X11L in brain compared to X11.…”

“…Recent gene ablation studies support the model that X11 and FE65 family proteins are involved in the regulation of APP metabolism [72-74, 93, 94]. Future studies will be required to evaluate the roles of for precise metabolism of APP [73]. The phosphorylation at Thr668 may function as a molecular switch that changes the binding preference of APP [112].…”

“…In double knock-out mice lacking both X11 and X11L, the -cleavage of APP and the accumulation of A peptides were increased in brain. One possible mechanism underlying these effects is that members of the X11 family of proteins might regulate the -cleavage of APP by anchoring APP outside of the detergent-resistant membrane fraction, thereby protecting APP from active -secretase -site-cleaving enzyme (BACE) [73] (Fig. 2A).…”

Deletions flanked by breakpoints 3 and 4 on 15q13 may contribute to abnormal phenotypes

“…28 Apba2 also interacts with amyloid precursor protein and suppresses its amyloidogenic cleavage. 29 Tight junction protein 1 (TJP1, OMIM 601009) encodes zonula occludens-1, a scaffolding protein involved in regulation of cell growth in a cell density-dependent manner and in stabilizing tight junctions and connecting them to the cytoskeleton. 30 Tjp1 has ubiquitous expression during development, with some later specialization in the CNS, eye, and heart.…”