Increased amyloidogenic processing of transgenic human APP in X11-like deficient mouse brain

Abstract

BackgroundX11-family proteins, including X11, X11-like (X11L) and X11-like 2 (X11L2), bind to the cytoplasmic domain of amyloid β-protein precursor (APP) and regulate APP metabolism. Both X11 and X11L are expressed specifically in brain, while X11L2 is expressed ubiquitously. X11L is predominantly expressed in excitatory neurons, in contrast to X11, which is strongly expressed in inhibitory neurons. In vivo gene-knockout studies targeting X11, X11L, or both, and studies of X11 or X11L transgenic mice have reported that X11-family proteins suppress the amyloidogenic processing of endogenous mouse APP and ectopic human APP with one exception: knockout of X11, X11L or X11L2 has been found to suppress amyloidogenic metabolism in transgenic mice overexpressing the human Swedish mutant APP (APPswe) and the mutant human PS1, which lacks exon 9 (PS1dE9). Therefore, the data on X11-family protein function in transgenic human APP metabolism in vivo are inconsistent.ResultsTo confirm the interaction of X11L with human APP ectopically expressed in mouse brain, we examined the amyloidogenic metabolism of human APP in two lines of human APP transgenic mice generated to also lack X11L. In agreement with previous reports from our lab and others, we found that the amyloidogenic metabolism of human APP increased in the absence of X11L.ConclusionX11L appears to aid in the suppression of amyloidogenic processing of human APP in brain in vivo, as has been demonstrated by previous studies using several human APP transgenic lines with various genetic backgrounds. X11L appears to regulate human APP in a manner similar to that seen in endogenous mouse APP metabolism.

Insulin Reverses the High-Fat Diet–Induced Increase in Brain Aβ and Improves Memory in an Animal Model of Alzheimer Disease

“…This observation is supported by previous in vitro studies showing a decrease BACE concentration following addition of insulin to cell culture (52). Second, insulin administration increased X11a (14% CD and 37% HFD), an adaptator protein that binds to APP and reduces its amyloidogenic cleavage (53,54), which was inversely correlated with insoluble Ab42 (r 2 = 0.13) (Fig. 4E and F).…”

“…To our knowledge, this is the first evidence for such a rapid effect of a treatment on soluble Ab. Our subsequent investigations identified changes in molecular markers implicated in Ab production, all altered by a single insulin injection, including increased a-APP, increased X11a, decreased BACE, and decreased autophagy-related proteins (53,55,72). Brain soluble Ab concentration is known to depend on neuronal activity (56,68,73), possibly through changes in amyloidogenic APP processing (68).…”

Membrane-Microdomain Localization of Amyloid β-Precursor Protein (APP) C-terminal Fragments Is Regulated by Phosphorylation of the Cytoplasmic Thr668 Residue

“…It is known that some of the APP-interacting proteins regulate the APP metabolism, including A␤ generation. Dysfunction of and/or aberrant regulation by these APP-interacting proteins may alter the APP metabolism without mutations in causative genes (9,10) and suggest(s) a possible cause for sporadic AD (11,12).…”

Cytoplasmic Fragment of Alcadein α Generated by Regulated Intramembrane Proteolysis Enhances Amyloid β-Protein Precursor (APP) Transport into the Late Secretory Pathway and Facilitates APP Cleavage

“…Furthermore, X11s function in the regulation of ␥-cleavage of APP CTF directly or indirectly (18) or of ␤-cleavage of APP indirectly (16). Importantly, X11s-KO mice showed a significant increase in endogenous A␤ generation in the brain and increased formation of amyloid plaques was observed in the brains of hAPP-Tg/ X11s-defective mice, indicating that X11s play an important role in APP regulation at various stages of APP metabolism and trafficking in vivo (16,20,21,34,35).…”

“…In vivo, X11L/X11␤ transgenic mice expressing human APP suppressed amyloidogenic processing of APP (19). Furthermore, X11L gene knock-out (X11L-KO) mice showed enhanced generation of endogenous A␤ in the brain (20), and human APP transgenic mice lacking the X11L gene exhibited enhanced amyloid plaque formation in the brain (21). However, the role of Alc␣ metabolites in APP metabolism and A␤ generation remain unclear in vivo.…”