Abstract
Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.
Highlights
Alzheimer’s disease (AD) is recognized as the most common form of dementia associated with aging [1]
Described by Alois Alzheimer in 1906 [4,5], AD is characterized by the presence of senile plaques (comprised of amyloid-β peptide (Aβ) [6,7,8]) and neurofibrillary tangles (NFTs) in the brain, causing marked glial activation and loss of neurons and synapses [12]
This model does not present a severe phenotype throughout its development thanks to compensation by other microtubule-stabilizing proteins [91,92]. These animals show brain atrophy, cognitive deficits, and motor disturbances [93,94]. These findings indicate that, tau has a deleterious role in neuropathological processes, its physiological functions are especially important at advanced ages
Summary
Alzheimer’s disease (AD) is recognized as the most common form of dementia associated with aging [1]. Based on a body of evidence, in 1992, John Hardy and Gerald Higgins proposed the amyloid hypothesis, stating that Aβ accumulation in the brain gives rise to AD pathogenesis, followed by the appearance of NFTs, neuronal death, and cognitive decline [13]. The rationale for this hypothesis was based on the identification of genetic modifications that altered Aβ production or the capacity of this peptide to aggregate [14]. All these studies suggest that the presence of Aβ is important in AD pathogenesis, other factors such as tau accumulation or neuroinflammation may be the main causes of neurodegeneration
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