Beta-amyloid racemized at the Ser26 residue in the brains of patients with Alzheimer disease: implications in the pathogenesis of Alzheimer disease.
Oligomeric and fibrillar beta-amyloid (Abeta) may be toxic in Alzheimer disease (AD), especially after post-translation modification cumulative over time. Racemization of Ser and Asp residues of Abeta in senile plaques (SPs) occurs as an age-dependent process in AD. We previously reported that Abeta1-40 racemized at Ser26 is soluble and susceptible to proteolysis yielding toxic [D-Ser26]Abeta25-35/40 fragments in vitro and in vivo. Here, we focus on the localization of racemized Ser26 residues in AD brains within the limbic system, the earliest site of AD histopathology. We developed antisera (20.1 and 22.7). each with epitopes within [D-Ser26]Abeta25-40. Two forms of truncated [D-Ser26]Abeta were detected either in SPs or within neurons in all 11 AD-affected brains, but not in age-matched controls. [D-Ser26]Abeta25/26-35 (detected by 20.1) was localized to plaque cores, extracellular neurofibrillary "ghost" tangles and vascular amyloid deposits. In contrast, [D-Ser26]Abeta25-40 (detected by 22.7) was observed in most neurons containing intracellular neurofibrillary tangles, but not in SPs. These results suggest [D-Ser26]Abeta]1-40, formed during aging, becomes soluble and diffuses from SPs. It is then proteolyzed to [D-Ser26]Abeta25-35/40, which is toxic and may contribute to the neurodegeneration. This hypothesis may explain the long lag between SP formation and neurofibrillary degeneration in AD brains.
Kubo
Takekazu
T
Biological Research Laboratories and Sankyo Research Institute, Sankyo, Shinagawa-ku, Tokyo, Japan
Kumagae
Yoshihiro
Y
Miller
Carol A
CA
Kaneko
Isao
I
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010361:Patients / Q000706:statistics & numerical data; D012694:Serine / Q000032:analysis* / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D012694:Serine