Tau aggregation and its relation to selected forms of neuronal cell death

Abstract

How neurons die in neurodegenerative diseases is still unknown. The distinction between apoptosis as a genetically controlled mechanism, and necrosis, which was viewed as an unregulated process, has blurred with the ever-increasing number of necrotic-like death subroutines underpinned by genetically defined pathways. It is therefore pertinent to ask whether any of them apply to neuronal cell death in tauopathies. Although Alzheimer’s disease (AD) is the most prevalent tauopathy, tauopathies comprise an array of over 30 diseases in which the cytoplasmic protein tau aggregates in neurons, and also, in some diseases, in glia. Animal models have sought to distil the contribution of tau aggregation to the cell death process but despite intensive research, no one mechanism of cell death has been unequivocally defined. The process of tau aggregation, and the fibrillar structures that form, touch on so many cellular functions that there is unlikely to be a simple linear pathway of death; as one is blocked another is likely to take the lead. It is timely to ask how far we have advanced into defining whether any of the molecular players in the new death subroutines participate in the death process. Here we briefly review the currently known cell death routines and explore what is known about their participation in tau aggregation-related cell death. We highlight the involvement of cell autonomous and the more recent non-cell autonomous pathways that may enhance tau-aggregate toxicity, and discuss recent findings that implicate microglial phagocytosis of live neurons with tau aggregates as a mechanism of death.

Concomitant Neuronal Tau Deposition and FKBP52 Decrease Is an Early Feature of Different Human and Experimental Tauopathies

“…3 and 4). This observation agrees with other studies showing the infrequent presence of Tau-D421 positive neurofilamentous tau aggregates in AD, familial FTLD-Tau [57][58][59], and in PSP brain neurons [60]. A study even reports the absence of Tau-D421 signals in PSP brains [61], nevertheless we detect in PSP brain neurons the same vesicular/lysosomal aspect of Tau-D421 immunoreactivity we observed in AD and familial FTLD-Tau brains suggesting that this kind of tau caspase and/or lysosomal processing might occur in PSP neurons and contribute to tau pathogenesis.…”

Neuropathology of Dementia Disorders

“…In aging and disease, the phosphorylation of tau and the formation of neurofibrillary tangles result in loss of the ability to perform these and other pivotal cellular functions. Neurofibrillary tangles are not specific to AD but also occur in normal aging and more than 30 different diseases 11 . In the context of dementia, tauopathy in other major neurodegenerative diseases includes subtypes of FTLD, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick disease, and FTD with parkinsonism due to MAPT mutations.…”

“…New to this pathologic framework is the criterion that the presence of amyloid is required even to diagnose low levels of AD pathology. By contrast, neurofibrillary tangles in the absence of amyloid are not consistent with AD pathology but rather indicative of primary age-related tauopathy (PART) or another tauopathy 11 . AD neuropathologic changes are described by an ABC score ( table 9-2 18 ) and further categorized as none or a low, intermediate, or high level of AD neuropathologic changes.…”

“…Neurofibrillary tangles are not specific to AD but also occur in normal aging and more than 30 different diseases. 11 In the context of dementia, tauopathy in other major neurodegenerative diseases includes subtypes of FTLD, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick disease, and FTD with parkinsonism due to MAPT mutations. Although most tauopathies have the accumulation of abnormally phosphorylated tau in neurons, an accumulation of tau in glial cells is also seen in aging and disease.…”

“…By contrast, neurofibrillary tangles in the absence of amyloid are not consistent with AD pathology but rather indicative of primary age-related tauopathy (PART) or another tauopathy. 11 AD neuropathologic changes are described by an ABC score (…”