Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain.
Hyperhomocysteinemia and beta-amyloid (Abeta) overproduction are critical etiological and pathological factors in Alzheimer disease, respectively; however, the intrinsic link between them is still missing. Here, we found that Abeta levels increased and amyloid precursor protein (APP) levels simultaneously decreased in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine. Concurrently, both the mRNA and protein levels of presenilin-1, a component of gamma-secretase, were elevated, whereas the expression levels of beta-secretase and presenilin-2 were not altered. We also observed that levels of phosphorylated APP at threonine-668, a crucial site facilitating the amyloidogenic cleavage of APP, increased in rats with hyperhomocysteinemia, although the phosphorylation per se did not increase the binding capacity of pT668-APP to the secretases. The enhanced phosphorylation of APP in these rats was not relevant to either c-Jun N-terminal kinase or cyclin-dependent kinase-5. A prominent spatial memory deficit was detected in rats with hyperhomocysteinemia. Simultaneous supplementation of folate and vitamin-B12 attenuated the hyperhomocysteinemia-induced abnormal processing of APP and improved memory. Our data revealed that hyperhomocysteinemia could increase Abeta production through the enhanced expression of gamma-secretase and APP phosphorylation, causing memory deficits that could be rescued by folate and vitamin-B12 treatment in these rats. It is suggested that hyperhomocysteinemia may serve as an upstream factor for increased Abeta production as seen in patients with Alzheimer disease.
Zhang
Chang-E
CE
Department of Pathophysiology, Key Laboratory of Neurological Disease of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Wei
Wei
W
Liu
Ying-Hua
YH
Peng
Jun-Hua
JH
Tian
Qing
Q
Liu
Gong-Ping
GP
Zhang
Yao
Y
Wang
Jian-Zhi
JZ
D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005492:Folic Acid / Q000494:pharmacology; D015870:Gene Expression; D020138:Hyperhomocysteinemia / Q000150:complications / Q000503:physiopathology*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008569:Memory Disorders / Q000209:etiology; D010766:Phosphorylation; D053764:Presenilin-1 / Q000378:metabolism; D053766:Presenilin-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014805:Vitamin B 12 / Q000494:pharmacology; D014803:Vitamin B Complex / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D053766:Presenilin-2; D012333:RNA, Messenger; D014803:Vitamin B Complex; D005492:Folic Acid; D053829:Amyloid Precursor Protein Secretases; D014805:Vitamin B 12