Date Published: August 21, 2011
Publisher: Impact Journals LLC
Author(s): Sathish Kumar, Jochen Walter.
Alzheimer’s disease (AD) is the most common form of dementia and associated with the progressive accumulation of amyloid β-peptides (Aβ) in form of extracellular amyloid plaques in the human brain. A critical role of Aβ in the pathogenesis of AD is strongly supported by gene mutations that cause early-onset familial forms of the disease. Such mutations have been identified in the APP gene itself and in presenilin 1 and 2. Importantly, all the identified mutations commonly lead to early deposition of extracellular plaques likely by increasing the generation and/or aggregation of Aβ. However, such mutations are very rare and molecular mechanisms that might trigger aggregation and deposition of Aβ, in the most common late onset AD are largely unknown. We recently demonstrated that extracellular Aβ undergoes phosphorylation by a cell surface-localized or secreted form of protein kinase A. The phosphorylation of serine residue 8 promotes aggregation by stabilization of β-sheet conformation of Aβ and increased formation of oligomeric Aβ aggregates that represent nuclei for fibrillization. Phosphorylated Aβ was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non-phosphorylated Aβ. Together, these findings demonstrate a novel molecular mechanism that triggers aggregation and toxicity of Aβ. Thus, phosphorylation of Aβ could be relevant in the pathogenesis of late onset AD. The identification of extracellular protein kinase A should also stimulate pharmacological approaches to decrease Aβ phosphorylation in the therapy and/or prevention of AD.
Alzheimer’s disease (AD) is the most common form of dementia in the ageing population and affects millions of people worldwide . At the neuropathological level, AD is characterized by neuronal cell loss and the combined presence of two lesions in the brain – extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) . The extracellular deposits contain aggregated Aβ peptides , while intraneuronal tangles are aggregates of hyper-phosphorylated forms of the neurofilament-associated protein tau . Evidence suggests that the pathogenesis of AD involves deleterious neurotoxic effects of both types of aggregates [5;6]. However, numerous studies strongly support a critical role of Aβ aggregates in the initiation phase of AD pathogenesis, while tau might mediate toxicity and impairment of neuronal function [5-9].
Increasing evidence suggests that phosphorylation of proteins involved in several neurodegenerative diseases and plays a serious role during the pathogenesis [67;112;113]. The role of phosphorylation in modulating the aggregation and fibrillogenesis of tau in AD and α-synuclein in Parkinson’s disease (PD) is currently a subject of intense investigation [103;114;115]. Our studies provide evidence that Aβ can undergo phosphorylation. Phosphorylation promotes conformational transition and formation of toxic aggregates. Further, phosphorylated Aβ aggregates could serve as endogenous seeds triggering further aggregation of soluble, extracellular Aβ into plaques in the brain. Phosphorylation stabilizes the Aβ against degradation by various proteases in vitro and in cell cultures (Kumar et al., Unpublished data). The stabilization of Aβ by phosphorylation might play a crucial role in AD pathogenesis, because it would eventually result in increased concentrations of this peptide in the brain. Therefore, inhibition of extracellular kinases or stimulation of Aβ dephosphorylation could be pursued as valuable targets to prevent or slow down the progression of AD. Further, the detection of phosphorylated Aβ in biological fluids could also be explored for evaluation as biomarkers. Together, phosphorylation of Aβ might have very important implications for AD pathogenesis and offer novel therapeutic avenues.