Phosphorylation of the amyloid β-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity

Abstract

Aggregation and toxicity of the amyloid β-peptide (Aβ) are considered as critical events in the initiation and progression of Alzheimer’s disease (AD). Recent evidence indicated that soluble oligomeric Aβ assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the Aβ sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization of oligomers of the wild-type Aβ remain unclear. Here, we identified an Aβ variant phosphorylated at Ser26 residue (pSer26Aβ) in transgenic mouse models of AD and in human brain that shows contrasting spatio-temporal distribution as compared to non-phosphorylated Aβ (npAβ) or other modified Aβ species. pSer26Aβ is particularly abundant in intraneuronal deposits at very early stages of AD, but much less in extracellular plaques. pSer26Aβ assembles into a specific oligomeric form that does not proceed further into larger fibrillar aggregates, and accumulates in characteristic intracellular compartments of granulovacuolar degeneration together with TDP-43 and phosphorylated tau. Importantly, pSer26Aβ oligomers exert increased toxicity in human neurons as compared to other known Aβ species. Thus, pSer26Aβ could represent a critical species in the neurodegeneration during AD pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1546-0) contains supplementary material, which is available to authorized users.

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

“…While substrate specificity of PATs/DHHCs and protein thioesterases is rather broad  some In addition to palmitoylation, other PTMs, including phosphorylation, ubiquitination, sumoylation and nitrosylation have been demonstrated to influence synaptic function and pathophysiology of neurodegenerative diseases [255][256][257][258][259]. Further, crosstalk among these PTMs has also been demonstrated to contribute to fine tuning of the regulation of synaptic protein functions [27,260,261].…”

Deposition of phosphorylated amyloid‐β in brains of aged nonhuman primates and canines

“…Interestingly, the clinical manifestation of AD symptoms correlates with the occurrence of modified Ab variants phosphorylated at serine residue 8 (pSer8Ab) (11). Phosphorylated Ab species have an increased propensity to aggregate (6), show higher resistance against proteolytic degradation (7) and exert increased neurotoxicity (9). Deposits with phosphorylated Ab variants have been observed in brains of transgenic mouse, human sporadic and familial AD cases (1,8,11).…”

Phosphorylation Interferes with Maturation of Amyloid-β Fibrillar Structure in the N Terminus

“…its at very early stages of AD (5), whereas phosphorylation at Ser 8 is detected in the later stages of the disease (6). Several aspects of protein activity are influenced by phosphorylation of neurodegeneration-related proteins (4).…”