Astrocytes make up a sizable fraction of the supporting cells of the brain, and undertake a wide range of tasks in order to maintain function. They supply metabolites needed for neural function, maintain other aspects of brain chemistry, provide structural support, and are a component of the blood-brain barrier, among many other activities. It has been noted that astrocytes tend towards greater inflammatory behavior in the aged brain, and like all cell populations a greater number of astrocytes become senescent in later life. Behaviors change in many other ways in response to the aged environment, some adaptive and some maladaptive. It remains an interesting open question as to what degree aging can be treated by simply forcing cells to behave as though they were young; answers should hopefully emerge from continued work on partial epigenetic reprogramming of living tissue, the imposition of a youthful epigenetic pattern of gene expression on aged cells.
In today's open access paper, researchers discuss two less drastic approaches to favorably changing the behavior of astrocytes in the aging brain. In one case, a small molecule is used to induce a lesser degree of inflammatory overactivation in astrocytes, leading to improved function in brain tissue in an animal study. In the other case, a gene therapy is used to enable astrocytes to manufacture more of a secreted extracellular matrix protein that is important to the creation and function of synaptic connections between neurons; levels of this protein decline with age and in neurodegenerative conditions. Again, this intervention improves function in aged brain tissue, as assessed in an animal study.
Astrocytes in Brain Aging and Neurodegeneration: Cellular Mechanisms and Interventional Strategies
We discuss how astrocyte aging contributes to cognitive decline and highlight emerging evidence on how targeting astrocytes, both genetically and pharmacologically, may rescue cognitive decline associated with aging and neurodegenerative diseases. Astrocytes produce several molecules that control synapse formation and function, which are decreased in the aging brain and in Alzheimer's disease models. In this context, recent studies indicate that astrocytes undergo significant molecular and functional remodeling during aging. Notably, astrocyte senescence has been associated with loss of lamin-B1, nuclear alterations, impaired synaptogenic and neuritogenic capacity, altered glutamate metabolism, and mitochondrial dysfunction, all of which may contribute to reduced neuronal support and circuit integrity. In parallel, recent advances have shown that astrocyte responses during aging also include diverse reactive states that vary according to brain region, microenvironment, and disease stage. Importantly, senescence-associated and reactive features are not mutually exclusive and may coexist or interact, further contributing to synaptic dysfunction and increased vulnerability to neurodegeneration.
Recent studies have emphasized the value of astrocyte phenotype and function-oriented strategies, such as restoring astrocytic metabolic and mitochondrial competence, regulating chronic inflammation, and re-establishing proper astrocyte-synapse interactions, rather than broadly suppressing astrocyte activation/reactivity. In parallel, advances in cell-type-targeted delivery and pharmacological modulation have strengthened the translational potential of astrocyte-centered interventions. In this context, we recently demonstrated that by modulating astrocyte phenotypes, either pharmacologically or through gene therapy, we can reverse cognitive decline associated with aging and in a preclinical model of Alzheimer's disease (AD).
Histone deacetylases (HDAC) are crucial enzymes involved in the regulation of gene expression through chromatin remodeling, impacting numerous cellular processes, including cell proliferation, differentiation, and survival. HDAC inhibitors (iHDAC) are small molecules that prevent the deacetylation of histones, thereby promoting a more relaxed chromatin structure and enhancing gene expression associated with neuroprotective pathways. To address the role of iHADC in AD, we have used the beta-amyloid (Aβ) oligomers (AβOs) toxicity model. AβOs are soluble oligomers of the amyloid-peptide that accumulate in AD brains and are considered an important toxin that lead to synaptic loss in AD. We previously found that AβOs target murine and human astrocytes, cause astrocyte activation and trigger abnormal generation of reactive oxygen species, which is accompanied by impairment of astrocyte neuroprotective potential in vitro. Recently, we have shown that the iHDAC LASSBio-1911 mitigates the effects of AβOs on synapse loss and cognitive decline in mice. This was mainly due to its ability to modulate the astrocyte phenotype.
Astrocytes from distinct brain regions contribute to synapse formation through the secretion of various synaptogenic molecules. Among these, the extracellular matrix protein, Hevin, secreted by astrocytes, has emerged as a key player. Hevin promotes the formation of excitatory synapses by bridging pre- and postsynaptic proteins. Recent evaluation of data set from AD animal models and patients demonstrated that Hevin is downregulated in both animals and patients' brain samples. We employed adenovirus-mediated overexpression of Hevin in hippocampal astrocytes of aged and APP/PS1 transgenic mice. The use of a GFAP (glial fibrillary acidic protein) gene promoter ensured astrocyte-specific expression of the transgene. Behavioral analyses revealed that Hevin overexpression not only ameliorated cognitive, synaptic, and behavioral deficits in APP/PS1 mice, but also improved performance in aged wild-type animals.
View the full article at FightAging
