Tau Biology and Tau-Directed Therapies for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is characterised by a progressive loss of cognitive functions. Histopathologically, AD is defined by the presence of extracellular amyloid plaques containing Aβ and intracellular neurofibrillary tangles composed of hyperphosphorylated tau proteins. According to the now well-accepted amyloid cascade hypothesis is the Aβ pathology the primary driving force of AD pathogenesis, which then induces changes in tau protein leading to a neurodegenerative cascade during the progression of disease. Since many earlier drug trials aiming at preventing Aβ pathology failed to demonstrate efficacy, tau and microtubules have come into focus as prominent downstream targets. The article aims to develop the current concept of the involvement of tau in the neurodegenerative triad of synaptic loss, cell death and dendritic simplification. The function of tau as a microtubule-associated protein and versatile interaction partner will then be introduced and the rationale and progress of current tau-directed therapy will be discussed in the biological context.

Fig. 1

The modified amyloid cascade hypothesis and the neurodegenerative triad in Alzheimer’s disease. The schematic indicates how oligomeric Aβ induces the neurodegenerative triad of synaptic changes, dendritic simplification and neuron loss via tau-dependent and -independent mechanisms. Sites of potential therapeutic interventions against tau pathology are indicated in blue colour. See text for detail. GSK3β glycogen synthase kinase 3β

Fig. 2

Transcript variants and functional organisation of tau. The exon structure of tau with official numbering is shown on top. The often used conventional nomenclature according to Andreadis et al. [138] is shown in brackets. Exons that are expressed in CNS tau are indicated in dark grey (constitutively present) and red (alternatively spliced). Exons, which are only present in the PNS form of tau are indicated in light grey. The functional organisation of the longest human CNS isoform (441 tau) is shown below. Phosphorylation sites that have been identified in PHF-tau by mass spectrometry according to [139] are indicated. Calpain and caspase-3 cleavage sites that have been implicated in producing neurotoxic tau fragments are shown according to [58, 140] (arrowheads). The repeat regions, which constitute the basic microtubule interacting unit, are indicated as R1-R4. CTR C-terminal region, MBR microtubule-binding region, MT microtubule, PHFs paired helical filaments, PRR proline-rich region