An Approach to Interfering in Mitochondrially Mediated Cell Death due to Amyloid-β in Alzheimer's Disease

While present thinking in the research community is leaning towards tau rather than amyloid-β as the primary cause of cell death and dysfunction in later stage Alzheimer's disease, it is still the case that too much amyloid-β is toxic to cells. Researchers here propose a treatment based on suppressing one of the mitochondrial mechanisms of programmed cell death that is triggered by the presence of amyloid-β. This is in many ways a classic example of what I consider to be a problematic focus in medical research: ignoring the root cause damage, the amyloid-β, in favor of tinkering with cellular mechanisms in the hope of improving the dysfunctional, damaged state of cells and tissues.

There are no doubt a hundred places in which one could reasonably try to intervene downstream of the presence of amyloid-β - and a good twenty of those are probably fairly independent of one another, requiring separate research and development project to address. But why build twenty projects when you could build one to achieve the same effect? Target the root causes. Don't mess with the downstream state. I wish that more of that philosophy of development was in evidence in the research community. Sadly it remains a minority viewpoint, barely worked on, judging by what I see in the output of the medical life sciences.

Alzheimer's disease (AD) is the most prevalent type of dementia in the developed world. Despite the enormous efforts made by the scientific community, an effective therapeutic strategy against AD has yet to be developed. The importance of mitochondrial dysfunction in the pathogenesis of AD and other neurodegenerative diseases has been increasingly recognized. A causal relationship has been found between mitochondrial dysfunction and amyloid β (Aβ)-induced neuronal and vascular degeneration. Indeed, mitochondrial pathology, oxidative stress, and energy metabolism impairment are implicated in the pathogenesis of AD, preceding formation of Aβ plaques, cell death, and memory loss.

Mitochondrial-specific therapies are emerging as promising therapeutic tools. It is interesting that mitochondrial therapies have shown beneficial effects in different models of neurodegenerative pathologies, where mitochondrial dysfunction and apoptotic cell death are known to be involved, such as AD, Parkinson's disease, and Huntington's disease.

Carbonic anhydrases (CA) are enzymes involved in the reversible conversion of carbon dioxide and water into bicarbonate and protons. They are present in all the vertebrates, showing different intracellular locations and regulating pH and ion transport. CA-VA and CA-VB have a mitochondrial localization. CA-II, known as cytoplasmic, was also recently shown to be increased in brain mitochondria in aging and neurodegeneration. CA inhibitors (CAIs) are used to treat a variety of disorders. In this study, we examine multiple mitochondrial pathways of amyloid toxicity in neuronal and cerebral endothelial cells (ECs), and evaluate CAIs methazolamide (MTZ) and, for the first time, its analog acetazolamide (ATZ), on specific Aβ-mediated pathways of mitochondrial dysfunction and apoptotic cell death. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function.

Due to the long-term use of MTZ and ATZ in chronic conditions, the efficacy and the safety of their systemic administration have been widely assessed, making clinical trials for CAIs in AD a concrete possibility. Our novel findings on the mitochondrial effects of MTZ and ATZ against neuronal and vascular amyloid toxicity justify the selection of these drugs as a therapeutic strategy for AD and cerebral amyloid angiopathy.



That is exactly the opposite approach to senolitics. And it sounds as a bad idea as it very likely promotes cancer and chronic inflammation. It might be useful in limited cases to preserve the neurons while cleaning amyloid plaque and some of the intra cellular junk, so the cells destruction will be cancelled...

Posted by: Cuberat at June 22nd, 2018 3:47 PM

Cuberat: While you can get rid of your senescent cells without problem, you can't get rid of your neurons! Killing neurons is exactly the wrong approach to treat AD. The medical problems associated with senescent cells are caused by the existence of senescent cells. The medical problems of AD are caused by the dying of neurons! You can't fight a fire with gasoline!

Posted by: Antonio at June 23rd, 2018 2:04 AM

Speaking of causality - everyone's probably seen this already:
Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus

SciShow even did a video:

AD is still very obviously a disease of aging, but what sets off the disease process? Does the virus somehow sense host aging and decide it is time proliferate in order to 'jump ship'? Does the immune system get a bit 'twtichy' as we get older, 'anticipating' intracellular pathogens (viruses, mycobacteria)to become more active?

It's hard to fault people for looking into something if they think it could be brought to clinic quickly.

Posted by: CD at June 23rd, 2018 8:34 AM

Bcl-xL is a longevity gene in mitochondria that if over-expressed allows survival of mitochondria and defends against apoptosis and keeps them healthy by not allowing a mitochondrial pore to form and spew out the contents of mitochondria. We know that this is a longevity gene because a Spanish study showed that centenarians have youthful high expression of the Bcl-xL gene protein while normally aging middle-age people have low expression of this health providing protein. Reference Borras 2016, Human Exceptional Longevity. I would think if we could get the mitochondria in brains and neurons to express youthful levels of Bcl-xL protein, we could reduce the development of AD. I'm not sure anyone is trying this approach to AD at present.

Posted by: Biotechy Marcks at June 24th, 2018 9:54 AM

PS: Another aspect in the development of AD regarding mitochondrial degeneration appears to be Calcium overload in the mitochondria. Bcl-xL blocks a mitochondrial inner membrane channel and prevents Ca2+ overload mediated cell death (Tornero, 2011, Plos One). Amyloid beta is a prooxidant molecule that creates oxidative stress in the mitochondria, calcium overload then causes death of the mitochondria. This process can be blocked if there is a high level of Bcl-xL in the mitochondria, which blocks the formation of a mitochondrial pore that would otherwise result in the death of the mitochondria.

Posted by: Biotechy Marcks at June 25th, 2018 8:33 AM

PS2: A recent study has indicated that calcium overload could be one of the keys to understandin and treating AD. Reference: Joey Sky, Jan.2, 2018, Nature News, Calcium imbalance in the brain linked to Alzheimer's. A team of researchers at the John Elrod lab at Temple University has been looking into this line of AD research.

Posted by: Biotechy Marcks at June 25th, 2018 9:04 AM

@CD: I just found another research article of relevance to mitochondria death and AD. Reference: Shoshan-Barmatz, May 2, 2018, Pharmacological Research, VDAC1 mitochondrial dysfunction and Alzheimer's. They hypothesize that when this protein over expresses, it kills the mitochondria and opens the mitochondrial pore. They also think VDAC1 may have involvement in type 2 diabetes and other diseases as well.

Posted by: Biotechy Marcks at June 25th, 2018 11:28 AM

Thanks for the article leads; they look interesting. At present I have an embarrassment of riches when it comes to readings and topics to explore so I will have to add them to the queue, but I do hope to get back to you on them at some point.

As for prioritization, I'll have to go with the whole intracellular parasite / host co-evolution and its relationship to senescence and lifespan thing since it's pretty involved and I'm already in it. While I'm not as lucky as you as far as longevity-associated SNPs go { quit hogging them! /jk }, I make up for that in fortuitously stumbling upon articles that seem like they were written just for me, such as this one that turned up this morning:

Dampened STING-Dependent Interferon Activation in Bats
Compared with terrestrial mammals, bats have a longer lifespan and greater capacity to co-exist with a variety of viruses. In addition to cytosolic DNA generated by these viral infections, the metabolic demands of flight cause DNA damage and the release of self-DNA into the cytoplasm. However, whether bats have an altered DNA sensing/defense system to balance high cytosolic DNA levels remains an open question. We demonstrate that bats have a dampened interferon response due to the replacement of the highly conserved serine residue (S358) in STING, an essential adaptor protein in multiple DNA sensing pathways. Reversing this mutation by introducing S358 restored STING functionality, resulting in interferon activation and virus inhibition. Combined with previous reports on bat-specific changes of other DNA sensors such as TLR9, IFI16, and AIM2, our findings shed light on bat adaptation to flight, their long lifespan, and their unique capacity to serve as a virus reservoir.
{ DNA sensors - another thing to look up... }

Last night I wondered if pathogens that stay latent but become active during senescence would be more prone to cross-species infectivity, since a senescing host is more likely to be eaten by a predator, which presents an opportunity for transfer.

Of course, this means I'll also have to put on the back burner something really weird and OT that I feel the need to share and further clutter up the comments section:

Did you know that there are sweet taste receptors in the hypothalamus?

Sweet Taste Receptor Signaling Network: Possible Implication for Cognitive Functioning

Posted by: CD at June 26th, 2018 9:55 AM

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