Supporting Evidence for Senolytics to be an Effective Treatment for Alzheimer's Disease

Neurodegenerative diseases are strongly associated with the buildup of protein aggregates, misfolded or altered amyloid-β, tau, α-synuclein, and so forth, wherein one altered molecule can encourage others to also alter, leading to solid deposits in brain tissue and a surrounding halo of toxic biochemistry that degrades cell function and kills cells. Much of the Alzheimer's research and development to date has focused on how to clear those aggregates; unfortunately success in clearance of amyloid-β in Alzheimer's disease has failed to produce meaningful benefits to patients.

It is possible that protein aggregates are a relevant target in the very early stages of neurodegeneration, but after the point at which the immune system becomes roused, and significant numbers of cells become senescent in response to a toxic environment rich the molecular waste of aggregated proteins, it no long matters whether aggregates are present or not. Senescent cells drive inflammation which drives further senescence and tissue dysfunction, in a feedback loop that leads to major loss of neurons and death.

Researchers have shown that the use of senolytic treatments capable of bypassing the blood-brain barrier and destroying senescent cells in the brain, such as the dasatinib and quercetin combination, reduces neuroinflammation and late-stage pathology in mouse models of tau aggregation. This strongly implicates senescent cells in the progression of inflammation in neurodegenerative diseases. The caveat in this sort of study is that the mouse models are highly artificial, as mice do not normally develop this sort of condition, but nonetheless: more senescent cells in the brain is demonstrably a bad thing, and removing them improves matters. A human trial of senolytics for Alzheimer's patients has started, but it will likely be some years before results are announced.

Today's research materials provide supporting evidence for the relevance of senescent cells in the brain to neurodegenerative disease. Along the way it touches on a debate that is ongoing: senescence is a state of growth arrest, so what does senescence look like in non-replicating cells such as neurons? Is it also a relevant, harmful process, or are the supporting cells in the brain more of a problem when they become senescent? Certainly there is good evidence for senescent microglia and astrocytes to be a major issue in older animals. Further, is it a good idea to be destroying senescent neurons, and do senolytic treatments that work in other cell types in fact achieve that goal? These and other questions remain to be answered. The mice end up better off, destruction of neurons or no destruction of neurons, but I'd imagine that a more definitive understanding will be sought for broader human use of senolytics.

Scientists Identify Malfunctioning Brain Cells as Potential Target for Alzheimer's Treatment

Research conducted 2018 found that senescent cells accumulated in mouse models of Alzheimer's disease where they contributed to brain cell loss, inflammation, and memory impairment. When the researchers used a therapy to clear the senescent cells, they halted disease progression and cell death. "However, until now, we didn't know to what extent senescent cells accumulated in the human brain, and what they actually looked like. It was somewhat like looking for the proverbial needle in a haystack except we weren't sure what the needle looked like."

Using sophisticated statistical analyses, the research team was able to evaluate large amounts of data. In total, they profiled tens of thousands of cells from the postmortem brains of people who had died with Alzheimer's disease. The researchers' plan was to first determine if senescent cells were there, then how many there were and what types of cells they were. They succeeded. The team found that approximately 2% of the brain cells were senescent and that the senescent cells were neurons, which are the fundamental units in the brain that process information and are the workhorses of memory. They also are the primary cells that are lost in Alzheimer's disease.

Next, the team sought to determine if the senescent neurons had tangles - abnormal accumulations of a protein called tau that can collect inside neurons in Alzheimer's disease. These tangles closely correlate with disease severity, meaning that the more tangles individuals have in their brains, the worse their memory. The researchers found that the senescent neurons not only had tangles but that they overlapped to the point that it was hard to distinguish between them.

Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology

Senescent cells contribute to pathology and dysfunction in animal models. Their sparse distribution and heterogenous phenotype have presented challenges to their detection in human tissues. We developed a senescence eigengene approach to identify these rare cells within large, diverse populations of postmortem human brain cells. Eigengenes are useful when no single gene reliably captures a phenotype, like senescence. They also help to reduce noise, which is important in large transcriptomic datasets where subtle signals from low-expressing genes can be lost. Each of our eigengenes detected ∼2% senescent cells from a population of ∼140,000 single nuclei derived from 76 postmortem human brains with various levels of Alzheimer's disease (AD) pathology.

More than 97% of the senescent cells were excitatory neurons and overlapped with neurons containing neurofibrillary tangle (NFT) tau pathology. Cyclin-dependent kinase inhibitor 2D (CDKN2D/p19) was predicted as the most significant contributor to the primary senescence eigengene. RNAscope and immunofluorescence confirmed its elevated expression in AD brain tissue. The p19-expressing neuron population had 1.8-fold larger nuclei and significantly more cells with lipofuscin than p19-negative neurons. These hallmark senescence phenotypes were further elevated in the presence of NFTs. Collectively, CDKN2D/p19-expressing neurons with NFTs represent a unique cellular population in human AD with a senescence-like phenotype.


anyone know off the top of their head the delivery method for getting d+q into the brain?

Posted by: GREGORY S SCHULTE at December 16th, 2021 4:48 PM

@GREGORY S SCHULTE: Both dasatinib and quercetin pass through the blood-brain barrier. So standard oral administration works. That was the approach used in animal studies in tauopathy models.

Posted by: Reason at December 16th, 2021 4:59 PM

Is it reasonable to assume that this insight will apply to Parkinson's as well?

Posted by: Matthew at December 16th, 2021 7:26 PM
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