Relationship between tau pathology and neuroinflammation in Alzheimer's disease

Abstract

Alzheimer's disease is a chronic, age-related neurodegenerative disorder. Neurofibrillary tangles are among the pathological hallmarks of Alzheimer's disease. Neurofibrillary tangles consist of abnormal protein fibers known as paired helical filaments. The accumulation of paired helical filaments is one of the most characteristic cellular changes in Alzheimer's disease. Tau protein, a microtubule-associated protein, is the major component of paired helical filaments. Tau in paired helical filaments is hyperphosphorylated, truncated, and aggregated. What triggers the formation of paired helical filaments is not known, but neuroinflammation could play a role. Neuroinflammation is an active process detectable in the earliest stages of Alzheimer's disease. The neuronal toxicity associated with inflammation makes it a potential risk factor in the pathogenesis of Alzheimer's disease. Determining the sequence of events that lead to this devastating disease has become one of the most important goals for the prevention and treatment of Alzheimer's disease. In this review, we focus on the pathological properties of tau thought to play a role in neurofibrillary tangle formation and summarize how central nervous system inflammation might be a critical contributor to the pathology of Alzheimer's disease. A better understanding of the mechanisms that cause neurofibrillary tangle formation is of clinical importance for developing therapeutic strategies to prevent and treat Alzheimer's disease. One of the major challenges facing us is singling out neuroinflammation as a therapeutic target for the prevention of Alzheimer's disease neurodegeneration. The challenge is developing therapeutic strategies that prevent neurotoxicity linked to inflammation without compromising its neuroprotective role.

Fig 1

Schematic representation of the 6 tau isoforms generated by alternative RNA splicing. The N-terminus contains zero, one, or two 29-aa inserts (pink) and, together with the proline-rich domain, forms the projection domain, which protrudes away from MTs. The C-terminus includes either three or four 18-aa-long imperfect repeats (blue) separated by 13- to 14-aa-long inter-repeats (green), and together they form the MT-binding domain. Abbreviations: aa, amino acid; MT, microtubule.

Fig 2

Model for the relation between neuroinflammation and tau pathology in Alzheimer's disease. We propose a sequence of events initiated by stimuli (physical, chemical, or infectious) that induce inflammation. Activated glia (microglia and astrocytes) release inflammatory factors, such as some prostaglandins (eg, prostaglandin J2), nitric oxide, interleukin 6, tumor necrosis factor alpha, and reactive oxygen species (eg, superoxide anion), that work in concert to induce neurotoxicity. One of the consequences is the impairment of the ubiquitin/proteasome pathway, which leads to an accumulation of ubiquitinated proteins. If these proteins cannot be cleared, the cells activate apoptosis. Caspase-mediated proteolysis results in the cleavage of tau (and other proteins), and this generates aggregation-prone protein fragments that, if not cleared by the autophagy/lysosomal pathway, aggregate and promote neurodegeneration. Injured neurons, in turn, initiate the production of signals (eg, extracellular adenosine triphosphate and β-amyloid plaques) that further propel glial activation. Over time, this feed-forward cycle of glial activation and neuronal injury results in progressive neurodegeneration leading to the development of symptomatic Alzheimer's disease.