Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is pathologically defined by extracellular accumulation of amyloid-β (Aβ) peptides generated by the cleavage of amyloid precursor protein (APP), strings of hyperphosphorylated Tau proteins accumulating inside neurons known as neurofibrillary tangles (NFTs) and neuronal loss. The association between the two hallmarks and cognitive decline has been known since the beginning of the 20th century when the first description of the disease was carried out by Alois Alzheimer. Today, more than 40 million people worldwide are affected by AD that represents the most common cause of dementia and there is still no effective treatment available to cure the disease. In general, the aggregation of Aβ is considered an essential trigger in AD pathogenesis that gives rise to NFTs, neuronal dysfunction and dementia. During the process leading to AD, tau and Aβ first misfold and form aggregates in one brain region, from where they spread to interconnected areas of the brain thereby inducing its gradual morphological and functional deterioration. In this mini-review article, we present an overview of the current literature on the spreading mechanisms of Aβ and tau pathology in AD since a more profound understanding is necessary to design therapeutic approaches aimed at preventing or halting disease progression.

Keywords: Alzheimer’s disease; amyloid-β; propagation; spreading; tau.

Figure 1

Intercellular transmission of pathological amyloid-β (Aβ) and tau proteins. Seeds of pathological proteins can be released at the presynaptic level: (1) in exosomes after the fusion of Multivesicular bodies (MVBs) with plasma membrane (PM); (2) in larger vesicles called ectosomes; (3) as naked protein freely crossing the PM; or (4) can be transferred via tunneling nanotubes. Mechanisms of up-take by recipient neurons include; (5) receptors-mediated endocytosis; (6) bulk-endocytosis; (7) fluid-phase translocation; (8) macropinocytosis mediated by heparan sulfate proteoglycans (HSPGs); and (9) fusion of large tau-containing large vescicles with PM. (10) Intraneuronal Aβ seeds can trigger or enhance the formation of tau pathological aggregates. The transmission process can be modulated by multiple factors, including glial cells.