Tau pathophysiology in neurodegeneration: a tangled issue

Neurodegenerative tauopathies are marked by their common pathologic feature of aggregates formed of hyperphosphorylated tau protein, which are associated with synapse and neuronal loss. Changes in tau conformation result in both loss of normal function and gain of fibrillogenicity that leads to aggregation. Here, we discuss the pathophysiology of tau and emerging evidence of how changes in this protein might ultimately lead to neuronal death. In particular, based on recent evidence, we propose that a non-apoptotic caspase-associated form of death is occurring in tauopathy.

Introduction

In 1906, Alois Alzheimer described neurofibrillary tangle (NFT) pathology and observed senile plaques in the brain of a demented patient [1]. These are the neuropathological hallmarks of the disease that now bears his name and, although much attention has recently been devoted to amyloid as the causative agent in Alzheimer's disease (AD), neurofibrillary pathology correlates better with cognitive decline in AD than amyloid pathology. The largest component of NFTs was identified in the 1980s as the tau protein leading to the term ‘tauopathy’ for diseases with neurofibrillary pathology and prompting the hypothesis that alterations in tau might have a causative role in neurodegeneration in AD 2, 3. Tau is also implicated in neurodegeneration in many other diseases (Table 1). Subsequently, associations of haplotypes including the tau gene locus with disease risk 4, 5, 6 and the discovery of mutations in the Tau gene that cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) 7, 8, 9, 10 have confirmed that tau dysfunction, indeed, leads to degeneration. These discoveries led to experiments investigating tau molecular genetics, structure, function and how they are disrupted during the disease process. Nonetheless, controversy still surrounds the question of how alterations in tau confer toxicity to the brain. We do not yet know whether NFTs cause cell death or whether a soluble form, perhaps oligomers of hyperphosphorylated tau, is toxic. Furthermore, the mechanism of cell death is unknown. Here, we discuss emerging evidence about cell-death pathways from studies of tau pathology and cell death in the living brain and summarize the basic biology of tau and how it is disrupted in tauopathy. We propose that neurons undergo a slow non-apoptotic but caspase-associated form of cell death in tauopathy.