Preventing Alzheimer's Associated Epigenetic Changes in a Mouse Model of the Condition

Hypothetically, if one could prevent all of the detrimental reactions a cell undergoes in response to a specific disease-causing agent, would that cure the resulting disease? Clearly some disease causing agents are just plain destructive, and further detrimental cellular reactions to that destruction are not the important component of the condition. Are there categories of condition in which the problem is largely a matter of inappropriate cellular reactions to an otherwise innocuous agent, however? In those cases, preventing that reaction could be a viable approach to therapy - with the caveat that a truly innocuous agent is an unlikely circumstance. All aspects of cellular biochemistry act in multiple ways, and that includes pathogens, persistent metabolic waste, excessive inflammatory signaling, and so forth. Blocking one detrimental reaction to an agent still leaves all of the other reactions in place, known and unknown.

Cell behavior is governed by epigenetic mechanisms that determine which proteins are produced and in what quantity. This is a complex, dynamic system of feedback between protein production, environment, and cell activity. Is it possible in principle and practice to adjust specific parts of the epigenetic system in order to steer cells away from a detrimental reaction involved in disease progression? Yes, as today's research materials illustrate. We will likely see much more of this class of approach in the future. It is analogous to widely used strategies such as blocking specific cell surface receptors or suppressing production of specific proteins. All attempt to interfere beneficially in the downstream effects of disease causing agents, in the reactions of cells, without addressing the agents themselves.

Memory deficits resulting from epigenetic changes in Alzheimer's can be reversed

Memory loss associated with Alzheimer's disease (AD) may be able to be restored by inhibiting certain enzymes involved in abnormal gene transcription, according to a preclinical study. Alzheimer's disease alters the expression of genes in the prefrontal cortex, a key region of the brain controlling cognitive processes and executive functions. By focusing on gene changes caused by epigenetic processes (those that are not related to changes in DNA sequences) such as aging, the UB researchers were able to reverse elevated levels of harmful genes that cause memory deficits in AD.

Transcription of genes is regulated by an important process called histone modification, where histones, the proteins that help package DNA into chromosomes, are modified to make that packaging looser or tighter. The nature of the packaging, in turn, controls how genetic material gains access to a cell's transcriptional machinery, which can result in the activation or suppression of certain genes. Researchers found that H3K4me3, a histone modification called histone trimethylation at the amino acid lysine 4, which is linked to the activation of gene transcription, is significantly elevated in the prefrontal cortex of people with AD and mouse models of the disease. That epigenetic change is linked to the abnormally high level of histone-modifying enzymes that catalyze the modification known as H3K4me3. Researchers found that when the AD mouse models were treated with a compound that inhibits those enzymes, they exhibited significantly improved cognitive function.

In making that discovery, the UB team also identified a number of new target genes, including Sgk1 as a top-ranking target gene of the epigenetic alteration in AD. Sgk1 transcription is significantly elevated in the prefrontal cortex of people with AD and in animal models with the disorder. Researchers found that abnormal histone methylation at Sgk1 contributes to its elevated expression in AD. Sgk1 encodes an enzyme activated by cell stress, which plays a key role in numerous processes, such as regulating ion channels, enzyme activity, gene transcription, hormone release, neuroexcitability, and cell death. The researchers found it is highly connected to other altered genes in AD, suggesting it may function as a kind of hub that interacts with many molecular components to control disease progress.

"In this study, we have found that administration of a specific Sgk1 inhibitor significantly reduces the dysregulated form of tau protein that is a pathological hallmark of AD, restores prefrontal cortical synaptic function, and mitigates memory deficits in an AD model. These results have identified Sgk1 as a potential key target for therapeutic intervention of AD, which may have specific and precise effects."

Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer's disease

Epigenetic aberration is implicated in aging and neurodegeneration. Using postmortem tissues from patients with Alzheimer's disease (AD) and AD mouse models, we have found that the permissive histone mark H3K4me3 and its catalyzing enzymes are significantly elevated in the prefrontal cortex (PFC). Inhibiting H3K4-specific methyltransferases with the compound WDR5-0103 leads to the substantial recovery of PFC synaptic function and memory-related behaviors in AD mice. Among the up-regulated genes reversed by WDR5-0103 treatment in PFC of AD mice, many have the increased H3K4me3 enrichment at their promoters. One of the identified top-ranking target genes, Sgk1 is also significantly elevated in PFC of patients with AD. Administration of a specific Sgk1 inhibitor reduces hyperphosphorylated tau protein, restores PFC glutamatergic synaptic function, and ameliorates memory deficits in AD mice. These results have found a novel epigenetic mechanism and a potential therapeutic strategy for AD and related neurodegenerative disorders.

Comments

@Reason

I'm a bit confused about your often-repeated overall stance on aging. Inter- and intra-cellular signaling obviously is very important-as you must admit, since you admit that elimination of senescent cells would be highly beneficial via a reduction of SASP, and not because of a significant reduction of cell-intrinsic damage. Cellular senescence is a almost entirely an issue of inappropriate inter-cellular signaling: a signaling program that is beneficial in some circumstances, but eventually causes harm to the organism in a post-reproductive part of the lifecycle, as per Williams' popular antagonistic pleiotropy model of aging.

Why not think that a great deal of the processes constituting the overall aging process are similar to the cellular senescence example? Steve Horvath's work reversing neural damage points in that direction, as does the Conboy's work on heterochronic parabiosis, and the fact that transplanting an aged cell into a young organism seems to revert the cell to a younger functional state.

Everyone's goal should be to end aging. We don't yet fully understand why we age. It seems silly to commit to a particular view or approach to aging before all the facts are in. I agree with you that the aging-as-program view is less intuitive, but it seems mad to rule out certain approaches to aging as based on a particular theoretical commitment.

Posted by: gheme at December 16th, 2020 6:21 PM

* I mean David Sinclair's work, not Steve Horvath

Posted by: gheme at December 16th, 2020 6:38 PM
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