Pyroglutamate‐modified amyloid β‐peptides – AβN3(pE) – strongly affect cultured neuron and astrocyte survival

Abstract

N-terminally truncated amyloid-b (Ab) peptides are present in early and diffuse plaques of individuals with Alzheimer's disease (AD), are overproduced in early onset familial AD and their amount seems to be directly correlated to the severity and the progression of the disease in AD and Down's syndrome (DS). The pyroglutamate-containing isoforms at position 3 [AbN3(pE))40/42] represent the prominent form among the N-truncated species, and may account for more than 50% of Ab accumulated in plaques. In this study, we compared the toxic properties, fibrillogenic capabilities, and in vitro degradation profile of Ab1-40, Ab1-42, AbN3(pE))40 and AbN3(pE))42. Our data show that fibre morphology of Ab peptides is greatly influenced by the C-terminus while toxicity, interaction with cell membranes and degradation are influenced by the N-terminus. AbN3(pE))40 induced significantly more cell loss than the other species both in neuronal and glial cell cultures. Aggregated AbN3(pE) peptides were heavily distributed on plasma membrane and within the cytoplasm of treated cells. AbN3(pE))40/42 peptides showed a significant resistance to degradation by cultured astrocytes, while fulllength peptides resulted partially degraded. These findings suggest that formation of N-terminally modified peptides may enhance b-amyloid aggregation and toxicity, likely worsening the onset and progression of the disease.

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

“…Additionally, A␤ pE3 is known to have a high aggregation propensity (54,55), increased stability (56), enhanced toxicity compared with fulllength A␤ (57), and dramatically reduced solubility at physiological pH-conditions (58). Our findings go along with the A␤ pE3 seeding hypothesis (20,54,57). Here, we further corroborate the importance of A␤ pE3-42 in the etiology of AD by demonstrating the effects of elevating A␤ pE3-42 in 5XFAD mice.…”

Role of water‐soluble amyloid‐β in the pathogenesis of Alzheimer's disease

“…3. The aggregates of Ab consist in a mixture of various peptides, having different N-and C-termini, that dictate the physical properties of Ab itself (Saido et al 1995;He & Barrow 1999;Russo et al 2002).…”

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

“…Notably, most A␤ peptides isolated from AD brains are posttranslationally modified and truncated (2-6), and some are proposed to be oxidized (7,8) or cross-linked at Tyr-10 (9). Although the pathogenic consequences of these modifications need to be resolved, most of them can stabilize A␤ assemblies, interfere with proteolytic degradation, and increase A␤ toxicity in vitro (7,8,10).One line of defense against toxic A␤ species could be neutralizing antibodies. Stimulating the production of A␤ antibodies by active immunization with synthetic A␤ (11) or administering monoclonal A␤ antibodies (12, 13) reduced amyloid pathology and inflammation and improved cognitive function in mouse models of AD (14).…”

“…Notably, most A␤ peptides isolated from AD brains are posttranslationally modified and truncated (2)(3)(4)(5)(6), and some are proposed to be oxidized (7,8) or cross-linked at Tyr-10 (9). Although the pathogenic consequences of these modifications need to be resolved, most of them can stabilize A␤ assemblies, interfere with proteolytic degradation, and increase A␤ toxicity in vitro (7,8,10).…”