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Erschienen in:
01.02.2015 | Editorial
Protein aggregation in Alzheimer’s disease: Aβ and τ and their potential roles in the pathogenesis of AD
Erschienen in: Acta Neuropathologica | Ausgabe 2/2015
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This issue of Acta Neuropathologica includes a cluster of three review papers focusing on amyloid β-peptide (Aβ) and/or τ-protein aggregates in Alzheimer’s disease (AD). Since the first description of the disease by Alzheimer [1], Aβ-containing amyloid plaques and τ-derived neurofibrillary tangles (NFTs) have been identified to represent the pathological hallmarks of AD [1, 6, 8]. These two types of protein aggregates share a number of biochemical features. Both form fibrils, which are the major compounds of amyloid plaques (Aβ fibrils) and neurofibrillary tangles (τ fibrils; NFTs). Both proteins were shown to undergo posttranslational modifications, such as phosphorylation, truncation and/or pyroglutamate formation in the AD brain. These modifications may accelerate the speed of aggregation in vitro. Moreover, Aβ has been shown to promote τ aggregation [5, 7], suggesting that protein aggregation represents a key starter and/or promoter of the disease. The ability of Aβ to functionally interact with τ may depend on other proteins such as N-methyl-d-aspartate (NMDA) receptors that act as molecular switches to induce neuronal dysfunction and neurodegeneration. Figure 1 provides a schematic representation of the roles of Aβ and τ as presented in this cluster. The clinical manifestation of AD is, thereby, associated with high levels of mature Aβ and τ aggregates widely distributed throughout the brain.
Fig. 1
Schematic representation of the potential roles of Aβ and τ in the pathogenesis of AD as covered in this cluster. a Aggregation and posttranslational modification of Aβ and the presence of intermediates and fibrils in the human brain is reviewed in detail by Thal et al. (this issue). A similar aggregation pattern for τ including its abnormal posttranslational phosphorylation leading to fibrillar aggregates finally forming NFTs is described in the review of Nisbet al al. (this issue). b The toxic effects of Aβ oligomers at the cellular level are discussed by Viola and Klein (this issue), that of τ and its interactions with Aβ by Nisbet et al. (this issue). Interactions of Aβ intermediates (i.e., oligomers and protofibrils) with τ may have influence on the generation of abnormal phosphorylated τ-protein via Fyn. Extracellular fibrillar amyloid may be maleficent due to its mechanical properties that limit diffusion within the extracellular space and that alter the integrity of the extracellular matrix (e.g., vessel wall destruction in cerebral amyloid angiopathy). c Intracellular NFTs may also act mechanically deleterious to neurons as they occupy their cytoplasm, displace cell organelles and finally lead to neuron death [2, 3, 9]
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