Fight Aging!

It is becoming apparent that cellular senescence in supporting cells of the brain is a significant contributing factor in the development and progression of neurodegenerative conditions such as Alzheimer's disease. Researchers have demonstrated that partial clearance of senescent microglia and astrocytes via the senolytic dasatinib, a small molecule that can pass the blood-brain barrier, reverses neuroinflammation and disease pathology in animal models. Here, researchers review what is known of the senescence of astrocytes, one of the largest group of supporting cells in the brain, in the context of Alzheimer's disease. Given the way that the evidence is shaping up, there is a decent chance that the best of the first generation of usefully effective Alzheimer's treatments will turn out to be senolytics that clear senescent cells in the brain.

Alzheimer's disease (AD) is a chronic degenerative disorder of the brain related to progressive decline of memory and cognition. The disease is characterized by brain atrophy, extracellular accumulation of beta-amyloid peptide (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, and loss of synapses and dysfunctions of neurotransmission, as well as neuroinflammation.

Many of the cellular pathologies of AD present on neurons, such as neuronal extracellular deposits of Aβ, intracellular deposition of NFTs, and Lewy bodies. These classical pathologies are still central to diagnosing AD. However, although neurons have significant correlations with AD, other cell types and factors in the brain may also contribute to cognitive decline during AD. Additionally, astrocytes are the major glial cells and are vital for the normal physiological functions of the central nervous system (CNS). They perform critical roles in regulation of homeostasis and metabolism of the neurons, mediating uptake and recycling of neurotransmitters. Astrocytes also play a key role in maintenance of the blood-brain barrier (BBB). They also act as modulators of synaptic plasticity and transmission, supporting the view that astrocytes play an integral role in the initiation and progression of cognitive decline and AD.

Aging is considered the most significant risk factor for the occurrence and development of AD. The incidence of AD has been shown to increase with advancing age and cellular senescence. Studies regarding to the link and role of senescence in age-related diseases have become increasingly common, and are gradually becoming a new research area. Transcriptome analysis of AD and the aged human brain showed neurons and other non-neuronal CNS cell types including astrocytes, microglia, and oligodendrocytes displayed senescence-associated phenotypes.

Senescent astrocytes showed decreased normal physiological function and increased secretion of senescence-associated secretory phenotype (SASP) factors, which contribute to Aβ accumulation, tau hyperphosphorylation, and the deposition of NFTs in AD. Astrocyte senescence also leads to a number of detrimental effects, including induced glutamate excitotoxicity, impaired synaptic plasticity, neural stem cell loss, and blood-brain barrier (BBB) dysfunction.

Thus, therapies to alleviate astrocyte senescence could prevent the onset of AD or delay its progress. In many age-related disorders such as osteoarthritis, atherosclerosis, and diabetes mellitus type 2, the removal of senescent cells of transgenic mice models has shown an impaired associated pathology and extended the healthy lifespan. Success has also been observed in a mouse model of tau-associated pathogenesis. This study was the first to demonstrate a causal relationship between glial senescence and neurodegeneration. In this study, accumulations of senescent astrocytes and microglia were found in tau-associated neurodegenerative disease model mice. Elimination of these senescent cells via a genetic approach can reduce tau deposition and prevent the degeneration of cortical and hippocampal neurons.

Most recently, it was shown that clearance of senescent oligodendrocyte progenitor cells in AD model mice with senolytic agents could lessen the Aβ plaque load, reduce neuroinflammation, and ameliorate cognitive deficits. This seno-therapeutic approach is currently being tested in neurodegenerative diseases and despite expected challenges and difficulties, more detailed investigation is warranted.

Link: https://doi.org/10.3389/fnagi.2020.00148