Evidence mounts for alternate origins of Alzheimer’s disease plaques

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Evidence mounts for alternate origins of Alzheimer’s disease plaques

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Results could explain why drugs designed to remove amyloid deposits have failed to stop disease

A breakdown in how brain cells rid themselves of waste precedes the buildup of debris-filled plaques known to occur in Alzheimer’s disease, a new study in mice shows.

The field argued for decades that such plaques, containing the protein amyloid beta, built up outside of cells as a crucial first step toward the brain damage observed in Alzheimer’s disease. Led by researchers at NYU Grossman School of Medicine and the Nathan Kline Institute, the new study challenges this idea, known as the amyloid cascade hypothesis.

The lastest study findings argue instead that neuronal damage characteristic of Alzheimer’s disease takes root inside cells and well before these thread-like amyloid plaques fully form and clump together in the brain.

Publishing as the cover article in the journal Nature Neuroscience online June 2, the study traced the root dysfunction observed in mice bred to develop Alzheimer’s disease to the brain cells’ lysosomes. These are small sacs inside every cell, filled with acidic enzymes involved in the routine breakdown, removal, and recycling of metabolic waste from everyday cell reactions, as well as from disease. Lysosomes are also key, researchers note, to breaking down and disposing of a cell’s own parts when the cell naturally dies.

As part of the study, researchers tracked decreasing acid activity inside intact mouse cell lysosomes as the cells became injured in the disease. Imaging tests developed at NYU Langone Health and Nathan Kline (to track cellular waste removal) showed that certain brain cell lysosomes became enlarged as they fused with so-called autophagic vacuoles filled with waste that had failed to be broken down. These autophagic vacuoles also contained earlier forms of amyloid beta.

In neurons most heavily damaged and destined for early death as a result, the vacuoles pooled together in “flower-like” patterns, bulging out from the cells’ outer membranes and massing around each cell’s center, or nucleus. Accumulations of amyloid beta formed filaments inside the cell, another hallmark of Alzheimer’s disease. Indeed, researchers observed almost-fully formed plaques inside some damaged neurons.

“Our results for the first time sources neuronal damage observed in Alzheimer’s disease to problems inside brain cells’ lysosomes where amyloid beta first appears,” says study lead investigator Ju-Hyun Lee, PhD.

“Previously, the working hypothesis mostly attributed the damage observed in Alzheimer’s disease to what came after amyloid buildup outside of brain cells, not before and from within neurons,” says Lee, a research assistant professor in the Department of Psychiatry and NYU Langone Health and research scientist at Nathan Kline.

“This new evidence changes our fundamental understanding of how Alzheimer’s disease progresses; it also explains why so many experimental therapies designed to remove amyloid plaques have failed to stop disease progression, because the brain cells are already crippled before the plaques fully form outside the cell,” says study senior investigator Ralph Nixon, MD, PhD.

“Our research suggests that future treatments should focus on reversing the lysosomal dysfunction and rebalancing acid levels inside the brain’s neurons,” says Nixon, a professor in the Department of Psychiatry and the Department of Cell Biology at NYU Langone, as well as director of the Center for Dementia Research at Nathan Kline.

Researchers say they are already working on experimental therapies to treat the lysosomal problems observed in their studies.

A recent study (published in April in Science Advances) by the NYU Langone team sourced one cause of the cell’s waste disposal problems to a gene called PSEN1. The gene has long been known to cause Alzheimer’s disease, but its additional role in causing the illness (through lysosomal dysfunction) is only now becoming clear.

Their recent work also showed that the neuronal damage in a PSEN1 mouse model of Alzheimer’s disease could be reversed by restoring proper acid levels in lysosomes.

This work is covered by United States Patent 9,265,735 that is directed to methods of treating Alzheimer's disease based on reversing lysosomal de-acidification, the underlying cause of waste buildup. The terms and conditions of the patent are being managed in accordance with the policies of the health system.

According to the National Institute on Aging, more than 6 million Americans, most of them age 65 or older, have dementia, a progressive loss of thinking, remembering, and reasoning, due to Alzheimer’s disease.

Funding for these studies was provided by National Institute of Health grants P01AG017617, P50AG025688, and R01AG062376.

Besides Lee and Nixon, other NYU Langone and Nathan Kline study investigators involved in this research are Dun-Sheng Yang, Chris Goulbourne, Eunju Im, Philip Stavrides, Ann Pensalfini, Cynthia Bleiwas, Martin Berg, Chunfeng Huo, James Peddy, Monika Pawlik, Efrat Levy, and Mala Rao. Additional co-investigators are Han Chan and Cedric Bouchet-Marquis, at Thermo-Fisher Scientific in Hillsboro, Ore.; and Mathias Staufenbiel, at the University of Tubingen in Germany.

Media Inquiries:

David March

212-404-3528

david.march@nyulangone.org

https://www.eurekalert.org/news-releases/954383
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Re: Evidence mounts for alternate origins of Alzheimer’s disease plaques

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Greyhound wrote: Thu Jun 02, 2022 7:48 pm Their recent work also showed that the neuronal damage in a PSEN1 mouse model of Alzheimer’s disease could be reversed by restoring proper acid levels in lysosomes.
interesting research. I wonder how they restored proper acid levels in lysosomes.
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Re: Evidence mounts for alternate origins of Alzheimer’s disease plaques

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This is a lysosomal approach already in clinical trials; beta-cyclodextrin is almost a natural product.

Trappsol® Cyclo™ mechanism of action is to remove cholesterol from the lysosome.
Cholesterol (‘adipose saccules’ /lipid droplets) was Dr. Alois Alzheimer's third neuropathological feature that he discovered in his research in the early 20th Century .


https://cyclotherapeutics.com/trappsol-cyclo/
Last edited by J11 on Sun Jun 19, 2022 2:27 pm, edited 1 time in total.
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Re: Evidence mounts for alternate origins of Alzheimer’s disease plaques

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Hi, This may not be the best place to ask this question, but I read the following article on Ab plaque the discussion includes liver toxins and infections, (CMV, HSV-1, B. burgdorferi, C. pneumonia and H. pylori) and wonder what others think about this idea?
https://www.frontiersin.org/articles/10 ... 00174/full
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Re: Evidence mounts for alternate origins of Alzheimer’s disease plaques

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floramaria wrote: Fri Jun 17, 2022 7:09 pm
Greyhound wrote: Thu Jun 02, 2022 7:48 pm Their recent work also showed that the neuronal damage in a PSEN1 mouse model of Alzheimer’s disease could be reversed by restoring proper acid levels in lysosomes.
interesting research. I wonder how they restored proper acid levels in lysosomes.
If we have the time we can try to wade through the patent and try to figure it out but that it is challenging for a mortal like myself who is a self learner.
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Re: Evidence mounts for alternate origins of Alzheimer’s disease plaques

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Greyhound wrote: Sun Jun 19, 2022 11:54 am
floramaria wrote: Fri Jun 17, 2022 7:09 pm
Greyhound wrote: Thu Jun 02, 2022 7:48 pm Their recent work also showed that the neuronal damage in a PSEN1 mouse model of Alzheimer’s disease could be reversed by restoring proper acid levels in lysosomes.
interesting research. I wonder how they restored proper acid levels in lysosomes.
If we have the time we can try to wade through the patent and try to figure it out but that it is challenging for a mortal like myself who is a self learner.
Ditto. Challenging for me too!
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Re: Evidence mounts for alternate origins of Alzheimer’s disease plaques

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Whoa! It is always a good idea to do your background reading. There will be a quiz.
Study looked at proton pump inhibitor use and AD risk. Apparently a connection was found.
The article then went on to explain how acidifying lysosomes relates to microglia ability to degrade beta-amyloid.
PPIs -> enter brain -> shut off proton pumps in lysosomes -> suppresses acidification in lysosomes -> more amyloid

"Microglia treated with an ammonia pulse wash for 72 h were able to degrade a significant amount of β-amyloid in a single day [8], indicating that artificial lysosomal acidification is capable of affecting the amount of β-amyloid in the acute phase"

Lysosomal acidification! Me want ammonia pulse wash .... What is ammonia pulse wash?


"Possible explanations of the involvement of PPIs in AD may find clues in experimental studies [8, 35]. Acidification of lysosomes determines the ability of microglia to degrade β-amyloid [8]. PPIs penetrate the blood–brain barrier in animals and can inhibit vacuolar-type H+–adenosine triphosphatase proton pumps of lysosomes [8, 9, 36], which suppresses the acidification of lysosomes [35]. As a result, PPIs may contribute to the inhibition of acidification, reduced β-amyloid degradation, and enhanced β-amyloid deposition. Of note, PPIs had a greater effect on AD risk in patients using concurrent H2-blockers in the present study, lending support to the theory that blocking acidification may be driving β-amyloid deposits in the brain. PPIs are consumed for long periods in conditions such as GERD, with the resultant exposure of the human brain to a substantial amount of PPIs [37]. Chronic consumption of PPIs may thus be a risk factor for AD [37]. Interestingly, short-term lansoprazole treatment in wild-type and AD transgenic mice dramatically increased β-amyloid levels in a dose-dependent manner [9]. Microglia treated with an ammonia pulse wash for 72 h were able to degrade a significant amount of β-amyloid in a single day [8], indicating that artificial lysosomal acidification is capable of affecting the amount of β-amyloid in the acute phase. In addition, PPIs have high binding and selective affinity for misfolded tau protein [38], indicating that PPIs may have a potential effect in the formation of neurofibrillary tangles of aggregated tau protein in addition to β-amyloid as the pathologic hallmarks of AD [2, 3]. In vitro and in vivo studies have shown that the sulfoxide scaffold found in PPIs has inherent affinity to neurofibrillary tangles in AD and related disorders (e.g., dementia with Lewy bodies and frontotemporal degeneration syndrome) [39]. Furthermore, recent experimental studies have demonstrated that PPI are potent and selective inhibitors of the acetylcholine-biosynthesizing enzyme, choline acetyltransferase, of which cholinergic dysfunction may cause major dementia disorders in the central nervous system [40] as well as infertility in the spermatic cholinergic system "

https://pubmed.ncbi.nlm.nih.gov/35773740/
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Re: Evidence mounts for alternate origins of Alzheimer’s disease plaques

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You can acidify lysosomes and this can greatly reduce beta-amyloid in 72 hours without activating a potentially dangerous immune response? What is forskolin?


"The data presented herein show that increased acidification of lysosomes may be the key factor that determines the ability of microglia to degrade fAβ. Microglia constitutively express a scavenger receptor, SRA, that can mediate the binding and uptake of fAβ

As shown here, microglia have sufficient levels of lysosomal proteases to degrade proteins effectively; moreover, the levels of most proteases are higher in microglia than in J774 cells, which can digest fAβ efficiently. However, microglia have weakly acidic lysosomes, which would decrease the activity of many lysosomal proteases and could lead to the inability to degrade fAβ effectively. Treatment with inflammatory agents acidifies microglial lysosomes and makes them able to degrade fAβ. Although treatment with inflammatory agents can cause many changes in microglia, it is striking that a pulse-wash treatment with a weak base that transiently acidifies lysosomes also facilitates significant degradation of fAβ. This suggests that lysosomal acidification is the key event that is required for fAβ degradation by microglia.


In the assays of fAβ degradation with the ammonia pulse-wash or the forskolin treatment, we could only transiently acidify the lysosomes. In our experiments, the lysosomes were acidified four times for about an hour each time during a 72-h degradation assay. Nevertheless, we were able to observe ∼40% degradation of fAβ as a consequence of these treatments.


In summary, we show that unactivated microglia do not degrade fAβ because they have weakly acidic lysosomes, and lysosomal acidification is a key downstream event leading to fAβ degradation by activated microglia. This may also be a key to the effectiveness of therapies to promote clearance of amyloid plaques by microglia, and treatments that acidify microglial lysosomes while minimizing other inflammatory reactions may be particularly beneficial.
"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1838985/
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Re: Evidence mounts for alternate origins of Alzheimer’s disease plaques

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Mouse model with oral forskolin:

" After a relatively short term of treatment (10 days), forskolin-treated transgenic mice showed restored nest construction ability (p < 0.05) and their sociability (p < 0.01). There was a reduction of Aβ plaque deposition in the cortex and in the hippocampus. Furthermore, expression of transforming growth factor β, glial fibrillary acidic protein, and Iba-1 in the cortex was reduced in the forskolin-treated group, suggesting regulation of the inflammatory response mediated by activated microglia and astrocytes in the brains of the APP/PS1 mice (p < 0.01). Taken together, these findings suggest that forskolin shows neuroprotective effects in APP/PS1 Tg mice and may be a promising drug in the treatment of patients with AD."

"In this work, we describe beneficial effects of oral treatment with forskolin in a transgenic mouse model of cerebral amyloidosis."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913438/

But cerebral amyloidosis is one of the important problems that have been identified in the amyloid mabs. Inflammation is started and then cerebral amyloidosis in AD can cause serious ARIA. What if forskolin pre-treatment could eliminate this risk?
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Re: Evidence mounts for alternate origins of Alzheimer’s disease plaques

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I have silent reflux, and I have avoided PPIs because of the association with dementia risk. It appears H2 blockers (like Pepcid) and calcium carbonate products that reduce acid (like Tums) either increase dementia risk, cardiovascular disease risk, or both. Does anyone have strategies for protecting the esophagus and larynx from reflux? I already wait at least 3 hours after eating to lie down, but I still have a hoarse voice that is caused by reflux.
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