Gain of function by phosphorylation in Presenilin 1-mediated regulation of insulin signaling

• Published in: Journal of neurochemistry 2012-06, Vol.121 (6), p.964-973
• Main Authors: Maesako, Masato, Uemura, Kengo, Kuzuya, Akira, Sasaki, Kazuki, Asada, Megumi, Watanabe, Kiwamu, Ando, Koichi, Kubota, Masakazu, Akiyama, Haruhiko, Takahashi, Ryosuke, Kihara, Takeshi, Shimohama, Shun, Kinoshita, Ayae
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Biological and medical sciences; Brain - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Down-Regulation; Female; Gene expression; Humans; Insulin; Insulin - metabolism; insulin receptor; Kinases; Male; Medical sciences; Mice; Mice, Transgenic; Middle Aged; Neurochemistry; Neurology; Organic mental disorders. Neuropsychology; Pathology; phophorylation; Phosphorylation; Presenilin 1; Presenilin-1 - metabolism; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptor, Insulin - metabolism; Signal Transduction - physiology
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2012.07741.x

J. Neurochem. (2012) 121, 964–973. We have recently reported that Presenilin 1 (PS1), a causative gene of familial Alzheimer disease (AD), down‐regulates the expression level of insulin receptor (IR) as well as its signaling through a γ‐secretase‐independent pathway. PS1 is phosphorylated by glycogen synthase kinase 3 β at the serine 353 and 357 residues. The main purpose of the present study was to clarify the effect of PS1 phosphorylation on IR/insulin signaling. Here, we demonstrate that the pseudo‐phosphorylation mutant of PS1 inhibited IR transcription and reduced IR expression compared with wild‐type PS1. Importantly, there was a decrease in expression of IR in AD brains, and the phosphorylation ratio of PS1 was negatively correlated with IR level in human brain samples. In the data from mouse models of AD, IR reduction was not observed at the pre‐Aβ deposition stage but became apparent in that of post‐Aβ deposition. Together with our previous reports, these results suggest that phosphorylated PS1 can promote the down‐regulation of insulin signaling, which may be a positive feed‐forward mechanism inhibiting insulin signaling. As insulin resistance is reported to be a risk factor for sporadic AD, this PS1‐mediated regulatory mechanism of brain insulin signaling may be causally associated with AD pathology. The function of phosphorylated Presenilin 1 has not been elucidated. We demonstrate that phosphorylated Presenilin 1 at the serine 353 and 357 residues down‐regulated the expression of insulin receptor compared with wild‐type Presenilin 1, thus suggesting that phosphorylated PS1 may play the crucial role in a positive feed‐forward cycle inhibiting insulin signaling. From our findings, insulin signaling dysfunction may be associated with the pathogenesis of Alzheimer disease.