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For Retail Landlords, Time to Look Beyond Gyms to Wellness – ConnectCRE

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June 12, 2020

Fitness clubs, once considered a less appealing option for retailer center owners, became one of the hottest tenant classes before stay-at-home mandates shuttered most of them amid the COVID-19 pandemic. Post-pandemic, the International Council of Shopping Centers (ICSC) advises landlords to consider not only gyms but also the broader spectrum of wellness tenants.

In a new report, ICSC says the concept of wellness is less fuzzy than you might think.

The Global Wellness Institute (GWI), a Miami-based organization that seeks to educate the public and private sectors about preventative health and wellness, defines wellness as the pursuit of activities, choices and lifestyles that lead to a state of holistic health. The report states.

Wellness involves not merely physical health, but also mental, emotional, spiritual social, and environmental dimensions, according to ICSC. It also has a dimension of spending power: globally, wellness represented a $4.5-trillion economy in 2019, according to the GWI. Domestically, interest in wellness has spread from the Western U.S. to other regions.

ICSC says that key wellness segments often found in shopping centers include personal care, beauty and anti-aging; healthy eating, nutrition and weight loss; fitness and mind-body; preventative and personalized medicine and public health; and traditional and complementary medicine. Consumers heavily oriented toward wellness buy a wide array of often complementary services and products that sustain their lifestyles, including health food; supplements, vitamins, and minerals; anti-aging and other treatments such as facials, body scrubs, electrolysis, microdermabrasion, chemical peels and laser treatments; and alternative medical regimens.

Whether the goal is maintaining appearance and beauty or extending or merely preserving ones life, this is an array that shopping center landlords are scrutinizing with more avid interest than ever, ICSC says.

An ICSC survey has found that 73% of U.S. adults say living a healthy, well-balanced lifestyle in terms of their physical and mental well-being is more of a priority for them today than in the past.

The same ICSC survey reported that 39% of U.S. adults visited wellness tenants in shopping centers during the past year. They averaged 12 trips to wellness services in shopping centers during this perioda figure that rises to 31 trips when those who didnt visit these tenants at all are excluded. Cost and proximity were their top motivating factors for choosing a facility.

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For Retail Landlords, Time to Look Beyond Gyms to Wellness

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Alternative APOE Gene Variants Associated with Different Diseases of Aging – JD Supra

The inherent, ineluctable unpredictability of biology can be the basis for biological patent claims being non-obvious (lacking the requisite "reasonable expectation of success"; see, e.g., OSI Pharmaceuticals v. Apotex) and for the greater quantum of disclosure necessary to satisfy the written description and enablement requirements of 112 (see, e.g., Amgen v. Sanofi), despite complaints from the life sciences patent bar that these increased requirements are improper doctrinally and unfair. These two different characteristics can be frequently in tension for patenting in the life sciences, it being difficult to maintain on the one hand that there is insufficient expectation of success for a claim to be obvious and on the other hand that deficiencies in disclosure can be appropriately supplemented by the knowledge of one of ordinary skill.

This unpredictability was illustrated in a paper recently published in Nature Medicine, entitled "Common germline variants of the humanAPOE gene modulate melanoma progression and survival." These authors* showed (somewhat paradoxically) that one variant of the human APOE gene (APOE2) was associated with a propensity for tumor cells to metastasize, while a different variant (APOE4), which has been known for several years to be associated with development of Alzheimer's disease (see Strittmatter et al., 1993, Proc. Natl. Acad. Sci. USA 90: 1977-81), exhibited a metastasis-inhibiting effect (and APOE2 itself can have a protective effect on development of late-onset Alzheimer's; see Corder et al., 1994, Nat. Genet. 7: 180-84).

The experiments were performed in mice expressing human APOE4 or APOE2 by genetic replacement of the mouse analogs. Differences in melanoma tumor growth in these two mouse strains carrying these different human APOE genes were shown by comparing mouse melanoma tumor growth as shown in this Figure:

(where YUMM3.3 and YUMMER1.7 are murine melanoma cell lines).

The protective effects against metastasis of APOE4 were compared with APOE2 in these mice was demonstrated by tail vein injection of B16F10 melanoma cells, an established metastasis animal model. The human APOE4-bearing mice had a phenotype of enhanced anti-tumor immune response and improved outcomes under PD1 immune checkpoint blockade.

Because APOE was known to have modulatory effects on immune response, flow cytometric analysis of APOE gene variants in mice was performed and showed "enhanced recruitment of CD45+ leukocytes in animals bearing various melanoma tumors in APOE4 mice compared with APOE2 mice." Proportions of immune suppressor cells (Ly6G+ granulocytic myeloid-derived suppressor cells) were found to be diminished in APOE4-bearing mice, while these mice showed increased proportions of antitumor effector cells such as natural killer (NK) cells and CD8+ T cells. These results were confirmed by single-cell RNA sequencing for detecting lineage-specific gene expression. Further experiments showed that T cell depletion "completely abrogated" differences in melanoma tumor growth between human APOE4- and human APOE2-bearing mice. The authors concluded that "[t]hese data suggest that APOEgenotype modulated both the abundance and the functional state of the tumor immune microenvironment, with theAPOE4variant eliciting an enhanced anti-tumor immune profile relative to theAPOE2 variant." These authors also showed that APOE4 suppressed melanoma cell invasion and endothelial recruitment (involved in angiogenesis), which was consistent with lower blood vessel density in APOE4 mice.

In addition to these mouse studies, the authors assessed APOE genotype association in melanoma human patients from The Cancer Genome Atlas (TCGA). Neither of these APOE variants was enriched in the database, which the authors said indicated neither gene was involved in increased melanoma incidence. However, APEO4 carriers had improved survival, with 10.1 years for these patients versus 2.1 years for APEO2 carriers. This outcome was surprising due to the reduced longevity associated with APOE4 carriers, which the authors attributed to the high rates of melanoma-associated death. These results demonstrated that "germline genetic variants of APOEdifferentially associated with survival in patients with advanced melanoma who were at increased risk for melanoma-associated death and metastasis."

PD-1 immunotherapy is a commonly used treatment for melanoma, and "APOE4mice survived significantly longer thanAPOE2mice upon anti-PD1 treatment, suggesting thatAPOE genotype modulates melanoma outcome also in the context of immunotherapy," according to the results shown in the paper. In humans, "APOE4andAPOE2carriers exhibited the longest and shortest survival outcomes, respectively, upon anti-PD1 therapy," consistent with the results in mice.

The final set of experimental results reported in this paper involved pharmacologic activation of APOE through liver X receptors, which are "nuclear hormone receptors that transcriptionally activate several genes implicated in cholesterol and lipid metabolism, includingAPOE." In mice, this effect was completely abrogated in APOE2 mice but showed "robust anti-tumor effects" upon treatment in APOE4 mice. The authors concluded from these results that "distinct APOEgenotypes elicited differential responsiveness to LXR agonistic therapy and might serve as potential genetic biomarkers for current clinical efforts investigating the use of LXR agonism in cancer therapy."

The authors provide the following context for the results set forth in their paper:

Our findings have several potential clinical implications. Most importantly, they suggest that common germline variants might serve as biomarkers to identify patients with melanoma who are at high risk for metastatic relapse and melanoma-associated death for treatment with adjuvant systemic therapy. Notably, these clinical association findings will need to be assessed in prospective studies. It will be important to also assess the effect of APOE genotype on the outcome of additional cancer types. More generally, our findings support the notion that hereditary germline variants in the same gene can positively or negatively affect future progression and survival outcomes and responsiveness to therapy in a common human malignancy.

Authors: Benjamin N. Ostendorfa,Jana Bilanovica, Nneoma Adakua,Kimia N. Tafreshiana,Bernardo Tavoraa,Roger D. Vaughanb & Sohail F. Tavazoiea

a Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USAb Department of Biostatistics, The Rockefeller University, New York, NY, USA

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Young Blood and Old Blood | In the Pipeline – Science Magazine

So lets do a non-coronavirus post for the weekend. Over the years, Ive sporadically reported on the (rather contentious) field of aging and its biochemical implications. Many readers will recall the results of the past few years that claim that infusion of young-animal plasma into aged animals seems to have many beneficial effects. Of course, this field is well stocked with controversy. Not everyone believes the results, from what I can see (although, for what its worth, there seem to be an increasing number of papers on it). If theyre real, not everyone thinks that they can be readily extrapolated to humans. And even if they can, it doesnt take very much thought to see a number of ethical implications as well.

There have been a couple of recent papers that will stir things up even more. This preprint from a multinational research team (UCLA and many others) details work on several methylation clocks of molecular aging. DNA is methylated (especially on cytosine residues) to a number of transcriptional effects, and the number and distribution of such methyl groups definitely change over the lifespan of most animals. The Horvath lab at UCLA has made a specialty out of this epigenetic research area for some years now, and the changes in DNA methylation with aging seem pretty well established (even if quantifying them is trickier). This new paper draws on a large number of rat samples, with an overall methylation clock detailed, as well as more specific ones for brain, liver, and blood tissue. The addition of an even larger set of human tissue samples provides two more cross-species methylation clocks as well. Previous work from the group has provided similar clocksfor mice, which correlate well with known lifespan-extending interventions such as caloric restriction (reviewed here).

This new preprint details the readouts of such clocks after treatment of two-year-old rats (and their various tissues) with a proprietary plasma preparation from a company called Nugenics Research (update: corrected spelling of the name). I dont think thats going to make publication of this paper in a journal any easier, because that preparation is resolutely not described in any detail at all in the paper, from what I can see. This is no indictment of the paper or its results, but it does make them rather difficult to reproduce, doesnt it? Two of the papers authors are founders and/or owners of Nugenix, and Horvath and another author are consultants for the company (all this, to be sure, is stated in detail).

At any rate, the effects of the plasma preparation on both the methylation signatures and on more traditional readouts of physiological function seem to be pretty dramatic, after two rounds of treatment in elderly rats. By the DNA methylation clock, the ages of the blood, heart, and liver tissue were basically halved (there was much less effect on the hypothalamus, interestingly). Markers of inflammation and oxidative stress went down significantly in the treated animals, and many other blood parameters changed for the better as well (HDL, creatinine, and more). The animals performed better in physical and cognitive tests (grip strength, maze test) with numbers approaching that of the young animals themselves. The authors say that this work supports the notion that aging can be systemically controlled, at least in part through the circulatory system with plasma as the medium.

Meanwhile, this paper has also just come out, which looks at whether such effects are due to factors coming in from the young animals or things being removed from the old ones. The authors, from UC-Berkeley and the California Pacific Medical Center, are looking at what they call a neutral blood exchange. They replace half the blood volume in mice (both young and old) with isotonic saline plus added albumin protein. The effect of this on the older animals was also significant, with noticeable improvements in wound-healing ability, neurogenesis, and fibrosis/fatty deposits in the liver. The younger mice were not really changed by the treatment. The authors tried several control experiments to make sure that this wasnt an effect being driven by added albumin protein, and it apparently isnt. They conclude that removal and substitution of old plasma is sufficient for most if not all observed positive effects on muscle, brain and liver in parabiosis-type experiments. It doesnt exclude the idea of there being beneficial factors in young plasma, but suggests that this is not the driver of many of the results seen. (It would be very interesting to check the DNA methylation status of various tissues before and after this treatment!)

The paper wastes no time in noting that therapeutic plasma exchange (TPE) is already an FDA-approved process (as witness convalescent plasma treatment in the current coronavirus epidemic), and it says that Phase II and III human trials are being planned on the basis of these results.That will be quite interesting to watch, says the 58-year-old dude writing this blog. Overall, I still find such results hard to believe, but at the same time they seem to be showing up from multiple experiments. This second paper especially seems to be a very testable hypothesis indeed. Thats a good thing, because in the end, its going to be reproducible human clinical data that decide whether this is real or not so Im glad that feasible experiments will allow such data to be collected. Something to watch. . .

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Could these senolytic drugs halt the spread of COVID-19? – Health Europa

Professor Michael P Lisanti, Chair in Translational Medicine at the University of Salford, has been an active research scientist for more than 30 years and is an expert in the field of cellular senescence. He tells HEQ about the potential of readily available, low cost, MHRA- and FDA-approved drugs to possibly treat and prevent the spread of COVID-19.

Senolytic drugs can be used to prevent or reverse ageing. There have been studies in mice that have shown that if you use a genetic trick, you can reverse ageing-associated disease characteristics but the problem is you cant do that in humans, so you would need a drug. We set out to identify drugs that would selectively kill senescent cells, but not harm normal cells; for this purpose, we developed a drug screen where we looked at various agents which prohibit cancer stem cell activity and we came across azithromycin, which selectively killed senescent cells with efficiency of nearly 97% and did not harm the normal cells. When we looked at the literature, we saw that patients with cystic fibrosis had been treated with azithromycin cystic fibrosis is similar to accelerated ageing as a disease, because theres a huge amount of inflammation and fibrosis and it dramatically increased their lifespan and their survival rates.

Fibrosis is normally an ageing-associated disease characteristic: its what kills patients with cystic fibrosis, because their lungs become stiff and can no longer expand and contract, in order to breathe. The azithromycin was also behaving as an antifibrotic, removing or preventing the formation of senescent myofibroblast cells; so we actually had proof In previous studies that our drug was actually a senolytic. If you reread the literature with senolytic glasses, you realise that the proof of its efficacy in humans is already there.

Another study in Japan looked at azithromycin based on its activity in cystic fibrosis patients and then applied these finding to patients with idiopathic pulmonary fibrosis. The control group survival rate in that paper was 25%, but on azithromycin it was nearly 80%. There is evidence in the published literature that its either preventing or removing fibrosis which is consistent with our data, but nobody thought about cystic fibrosis or about idiopathic pulmonary fibrosis as diseases of senescence: they thought it was preventing the formation of the myofibroblasts, but we believe it was killing the myofibroblasts, which are now known to be senescent cells.

The reason you want to get rid of the senescent cells is because they are actually contagious. They secrete IL-6, which is an inflammatory mediator; and they make other cells senescent by diffusion of the inflammatory mediators, which explains why as you get older you accumulate more and more senescent cells. By the time youre 40 or 50 years old, you have aches and pains and you feel stiffness: these are a symptom that you are beginning to accumulate senescent cells.

All of this is very reminiscent of what happens in patients with COVID-19. Fatality rates are much higher in older patients and in patients with ageing-associated diseases, such as diabetes or coronary artery disease. IL-6 levels have been shown to be the best predictor for whether or not a patient will to wind up on a respirator and these patients may die from inflammation in the lung and the resulting fibrosis. It all sounds similar to a very acute episode of either cystic fibrosis or of idiopathic pulmonary fibrosis.

The virus has something called a host receptor, which allows the virus to bind the surface of the cells and then get internalised. For COVID-19, there are two proposed host receptors: one is CD-26, which is a marker of senescence; and the other one is ACE-2, which is also increased during senescence. This would suggest that the virus is preferentially targeting cells with markers of senescence.

We think of senescent cells as old and not very energetic, but they have to secrete a lot of inflammatory mediators, like IL-6, so they actually have very active protein metabolism and they do a lot of protein synthesis IL-6 is a protein and they produce inflammatory mediators of the senescence associated secretory phenotype (SASP). Therefore, the virus would want to invade a cell that is better at protein synthesis in order to make more copies of itself and the necessary viral spiked glycoproteins, to package the viral RNA or DNA for viral replication. This virus is seeking out the cells that are the best at making protein, to make more copies of itself, so it gets in the cell and takes over.

The predilection for fatalities in patients with advanced chronological age suggests there is a connection with senescence; and azithromycin, which appears to be working in clinical trials, is a senolytic and an antifibrotic. Certain antibiotics of the azithromycin class of which there are many are inhibitors of protein synthesis. The same is true of tetracyclines like doxycycline. These drugs would inhibit protein synthesis, so they would block IL-6 production and also block viral replication. Azithromycin has been shown to inhibit Zika virus and Ebola virus replication; and doxycycline has been shown to inhibit Dengue virus replication. Any drug which is a protein synthesis inhibitor, like certain classes of antibiotics, would also inhibit viral replication not because of any characteristics specific to the virus, but because its inhibiting protein synthesis, which is required for their viral replication.

The question, then, is why we cant use these drugs now in the clinic. In the United States, if a drug is prescribed off-label, its perfectly legal: the FDA approves a drug after Phase 1, Phase 2 and Phase 3 clinical trials for a particular indication. Then because the drug already went through Phase 1, which is a safety trial, it can be legally prescribed for any other disease indication off-label. The FDA will not actually have to directly approve doxycycline or azithromycin for treatment of COVID-19, because doctors can already prescribe it.

In a time of crisis, we need to practise what people are calling battlefield medicine, where we think outside the box. Theres already evidence in the published literature that these antibiotics have the protein synthesis inhibition side effect and have already been shown to inhibit viral replication. The problem in this country is people are rightfully afraid of antibiotic resistance. Its the kind of thing that has been ingrained in the mindset of doctors in the UK. However, I think we need to rethink the whole use of antibiotics to target viral infections. In fact, if you look in the literature for herpes virus (HSV), its already been shown that erythromycin, which is another protein synthesis inhibitor, is used either orally or as a cream to treat herpes outbreaks.

If we could give NHS workers either doxycycline or azithromycin prophylactically, the viral load would likely be gone or severely diminished. This would prevent the spread of the virus from one person to another, protecting clinicians against people who come to the hospital; and could also be used to treat patients. But, I think the key here is to avoid the fibrosis and the inflammation, which starts with the fever. When a patient comes down with a fever, they should immediately give them the doxycycline or the azithromycin, which will shut down IL-6 production and shut down the viral replication; so the patient is less likely to transmit the disease to healthcare workers.

All these drugs are very inexpensive the cost of doxycycline is 10 pence a day; azithromycin is also very cheap, because it came off patent in 2017 so these drugs could be used for prophylaxis and for treatment. Then potentially we could relax some of the social distancing and we could all go back to work. The problem is were not going to have vaccines for another 12 to 24 months, so we need something now thats already safe, thats MHRA- or FDA-approved for at least one indication. It may be something that can be used in conjunction with social distancing: some people dont have extra space in their house where they can really isolate, so then they could take an antibiotic like doxycycline or azithromycin to reduce viral loads. This would reduce the stress on the healthcare system, because if you treat people in the early stages and it works, they wont get to the ventilator stage and the problem is when you get to the ventilator stage, the patients lungs have effectively turned to cement from all the fibrosis, so the chances of getting people off the ventilator is rather low. Its very serious once you get to the ICU, so you want to prevent the onset of respiratory symptoms, by treating patients as soon as possible with an antibiotic that will shut down viral replication.

Doxycycline is the number one drug prescribed worldwide for any indication: its used for malaria, its mainly used for acne; and people will take it for six months at a time without any real issues, except maybe some stomach upset. People with acne rosacea take it for their whole life, especially in very disfiguring cases usually they recommend a drug holiday for a week or two, every six months. Doxycycline was approved first in 1967. Its not a senolytic, but it does inhibit IL-6 and it inhibits viral replication; and it has been shown by other people to be an anti-ageing drug as well. Both of these drugs are very cheap; and they should be in abundant supply worldwide.

SARS-CoV-1, the precursor for COVID-19, shows the same pattern of infection. They conducted experiments in humans and mice and saw that, for example, young mice will become infected, but it doesnt cause any real disease there is no inflammation or fibrosis; and a very mild pneumonia but if they use older mice aged 12 to 14 months, they see very severe inflammation, fibrosis and death. This is due to the induction of a very strong inflammatory response, which includes the IL-6. This original mouse model could be used to test this hypothesis regarding senolytics, but as these drugs are already FDA-approved, we can do that in parallel. The problem is its a question of time; and the longer we wait, the more people are infected, when we could just shut it down now. We could use patients already in hospital, you would have instant clinical trials. This is battlefield medicine. We should take advantage of the patient population with drugs that have very few side effects, and conduct clinical trials on a large scale.

I think people are in a state of helplessness. They dont know what to do, and the solution could be right under our noses. What were doing is not working, for many patients, and we need to change something; and the first step would be propagate the idea of field clinical trials. We can record all the data from the treatment of the patients as it progresses thousands of people have the disease and it could be a multicentre trial, the most important thing is to get something going now.

Much research into the treatment of COVID-19 is currently focused on the drugs chloroquine and azithromycin; and the FDA has granted an emergency licence for the use of chloroquine to treat COVID-19 patients. The European Medicines Agency has not yet followed suit, asserting that more research should be conducted; and some researchers have highlighted concerns over toxicity issues associated with chloroquine and its derivative, hydroxychloroquine.

Patients who are prescribed chloroquine or hydroxychloroquine normally would have to take a test for a glucose-6-phosphate dehydrogenase deficiency (G6PD) [an hereditary condition which increases the risk of haemolysis when chloroquine is administered]; and there are other issues with both chloroquine and hydroxychloroquine. I think the side effects may outweigh the benefits, because its not an inhibitor of viral replication; its an inhibitor of viral entry. If the patient is already sick, they already had the viral entry, then chloroquine will not necessarily shut down the viral replication. It only works for patients who have not already been infected.

In the clinical data from the French trial of hydroxychloroquine and azithromycin, the chloroquine did relatively little by itself and that has been called into question in terms of the effects. The combination with azithromycin was much more effective, but they didnt test azithromycin alone, which would probably be sufficient; because even if viral entry does occur, as long as the viral replication is inhibited, the virus will not propagate. We believe that the hydroxychloroquine isnt necessary; and we can reduce the risk to older patients by eliminating the hydroxychloroquine.

Azithromycin has some very mild side effects, but theyre not very prevalent; if they had been prevalent the drug would have been pulled off the market. There was some controversy as to the reproducibility of the studies regarding its side effects: multiple studies were done and some are positive, some are negative, so theres still a warning out there but the side effects only really occur with high doses of azithromycin, which would not be needed in this case. If azithromycin did cause problems for a patient they could switch to doxycycline, or they could start with doxycycline in the first place. These are just two examples of classes of drugs; there are other drugs which inhibit protein synthesis: erythromycin is in the same class as azithromycin, and it inhibits protein synthesis. It doesnt have the senolytic activity, but it would still inhibit the IL-6 and the viral replication.

The same is the case for the tetracyclines these are classes of drugs which are relatively similar and interchangeable, so if we run out of doxycycline, we would still have minocycline, tetracycline and all these other variations which have a similar effect on protein synthesis. The main issue with doxycycline is patients can experience some stomach upset or some nausea, but this can be alleviated by using a probiotic.

That would be the primary role of these drugs. Based on the results of clinical trials, the NHS could implement its usage. For example, ICU staff could receive it first, as they are in contact with patients that pose the most severe risk. Hospital staff right now are probably terrified of catching it, so why not take a prophylactic antibiotic, which has a chance of preventing infection? Im sure theyre doing a great job taking care of the patients, but it is traumatic to be under all this stress constantly. Its very stressful to be in such a high pressure situation, where youre afraid for your own life, but youre also trying to help other people at the same time. Then, you have your family at home and you dont want to also make them sick either. Healthcare workers are the people who are at the greatest risk; and already weve seen a reduction in NHS staff levels around one in four NHS staff are not at work, because they have either been infected or are isolating because they have symptoms.

We dont want to lose too many of the doctors and nurses in this crisis, so this would be helpful for everyone especially for preventing the further spread to shut down viral replication and contagion. Anything that can be done to reduce the viral load will reduce the contagion. They can do trials with young healthy volunteers who are asymptomatic, but it would be better to do it with the NHS staff who would need it most as a preventative approach for prophylaxis. We have recently proposed and published this prophylaxis strategy in a Letter to the Editor at the British Medical Journal (BMJ), which is widely read by GPs and consultants in the UK.

1 Letter to the Editor, British Medical Journal: https://www.bmj.com/content/368/bmj.m1252/rr-20

2 Lisanti, Sotgia et al. (2020). Senescence, ageing and potential COVID-19 treatments. Aging-US. https://www.aging-us.com/article/103001/text

Professor Michael P Lisanti, MD-PhD, FRSA, FRSBChair in Translational MedicineSchool of Science, Engineering & EnvironmentUniversity of Salford+44 (0)1612 950 240M.P.Lisanti@salford.ac.uk

This article is from issue 13 of Health Europa. Clickhere to get your free subscription today.

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Janus-Faced PCL2? Alzheimer’s Risk Protein Toggles TREM2 and TLR Pathways – Alzforum

12 Jun 2020

Rare variants in TREM2 and PCLG2 influence a persons odds of developing Alzheimers disease, but that is far from all the two genes have in common. According to a study published June 8 in Nature Neuroscience, phospholipase C 2 acts downstream of TREM2 in a signaling pathway that supports critical microglial functions. Using human microglia derived from induced pluripotent stem cells, researchers led by Joseph Lewcock at Denali Therapeutics in South San Francisco reported that knocking out either gene product prevented the immune cells from efficiently processing lipids and neuronal debris. The researchers also found that, independently of TREM2, PLC2 is involved in a pro-inflammatory side hustle dictated by toll-like receptors, which, it so happens, is exacerbated by intracellular lipid build-up. Taken together, the findings strongly implicate faulty microglial lipid handling in the etiology of AD, and support therapeutic strategies that aim to rev up TREM2 signaling.

Using an impressive array of experimental conditions in gene-edited iPSC-microglia, [the authors] demonstrate that PLC2 is a downstream effector of TREM2 and a regulator of lipid metabolism. This exciting discovery directly connects PLC2 to well-established AD pathways involving APOE, TREM2, and microglial activation, commented Rik van der Kant, Vrije University, Amsterdam (full comment below). Florent Ginhoux of the Agency for Science, Technology and Research in Singapore, agreed. The study elegantly links TREM2 and PLC2 signaling pathways, and offers mechanistic insight into how variants in these genes affect the pathophysiology of AD, Ginhoux wrote (full comment below).

Double Dealing. When triggered by TREM2, PLC2 supports lipid metabolism and survival (left). When triggered by TLRs, PLC2 triggers inflammation. In TREM2 KO microglia (right), lipids accumulate and this exacerbates the pro-inflammatory, TLR-driven pathway. [Courtesy of Andreone et al., Nature Neuroscience, 2020.]

Since the discovery, in 2012, that rare variants in the coding region of TREM2 triple the risk of AD, researchers have pegged the receptor as supporting myriad microglial functions, including phagocytosis, walling off A plaques, and promoting an anti-inflammatory, neuroprotective environment (May 2016 news; Apr 2017 conference news;Jul 2018 conference news).

Separately, researchers discovered a rare variant in phospholipase C 2 (PLCG2) that protects against AD (Aug 2017 conference news on Sims et al., 2017). PLCs are a large family of intracellular enzymes that cleave the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3), a process that facilitates calcium signaling. In the brain, the 2 isoform is predominantly expressed by microglia, and initial studies suggest that the protective variant munches phospholipids with more gusto than the common one does (Zhang et al., 2014; May 2019 news).

Might the functions of TREM2 and PLC2 intersect in microglia? To study this question, co-first authors Benjamin Andreone and Laralynne Przybyla derived human microglia. They wove together elements from three recently developed protocols to coax so-called induced microglia (iMGs) from induced pluripotent stem cells (Muffat et al., 2016; Pandya et al., 2017; McQuade et al., 2018). They then used CRISPR to wipe out expression of TREM2 or PLCG2 in these cell-based models.

Under normal conditions, iMGs missing either TREM2 or PLCG2 appeared healthy and viable. When the going got toughi.e., when growth factors were depleted from the culture mediaboth types of knockout suffered a similar fate, dying sooner than their wild-type counterparts. The transcriptomes of each of the two iMG knockouts also differed from those of wild-type cells in similar ways. Specifically, half of the genes differentially expressed in TREM2 KO iMGs were similarly affected in PLCG KO iMGs. These common genes were part of signal transduction pathways downstream of DAP12, the adaptor protein that mediates TREM2 signaling. Using biochemical approaches, the researchers ultimately pieced together a signaling cascade by which lipids activate TREM2, leading to the phosphorylation of Syk2, which directly interacts with PLC2, unleashing its phospholipase activity and downstream signaling events.

Disabling the pathway, either by knocking out TREM2 or PLC2, had a dramatic impact on the processing of lipids, including cholesterol-laden myelin. All microglial lines in this study readily engulfed this type of fluorescently labeled debris; however, while wild-type cells had largely disposed of it after four days, TREM2 or PLCG2 knockouts were still chock-full of it by then. Tellingly, perhaps, the knockout cells failed to ramp up expression of several lipid processing genes in response to the myelin challenge.

Choking on Lipids? Wild-type microglia (left) readily digested lipids after treatment with myelin, while microglia lacking PLCG2 (middle) and TREM2 (right) accumulated the lipids. [Courtesy of Andreone et al., Nature Neuroscience, 2020.]

Lipidomics experiments revealed that the knockouts became burdened with a backlog of several subtypes of unprocessed lipid, including free cholesterol, cholesteryl esters, and myelin-derived ceramides. Similarly, in co-culture experiments with iPSC-derived neurons, both types of microglial knockout were unable to properly digest detritus from injured axons.

How might AD risk variants shift these phenotypes? The researchers generated iMGs that expressed the R47H variant of TREM2, or the protective P522R variant of PLCG2. As might be expected from prior findings on these variants, the R47H-TREM2 iMGs processed lipids more sluggishly than wild-type, whereas the P522R-PLCG2 microglia more deftly disposed of them than wild-type. Together, the findings support the idea that TREM2 and PLCG2 variants influence AD risk via lipid metabolism.

Lest a reader be tempted to tie a neat little bow on this set of results, here comes the twist: PLC2 also takes marching orders from toll-like receptors. This was previously reported in peripheral immune cells. The Denali researchers found the same in iMGs, as PLCG2 knockouts failed to mount a pro-inflammatory response to the TLR2 ligand zymosan.

Interestingly, the same pro-inflammatory cytokines that were down in response to zymosan in PLCG2 knockout iMGs were up in TREM2 knockout iMGs. For example, compared with wild-type iMGs treated with zymosan, PLCG2 knockouts secreted 50 percent less IL-1, while TREM2 knockouts secreted 64 percent more.

The same pattern emerged when the researchers used the TLR4 ligand LPS to trigger the microglial NLRP3 inflammasome, which itself has been tied to AD (Nov 2019 news). Loading up the microglia with myelin prior to triggering the inflammasome dramatically enhanced the inflammatory response in TREM2 KO iMGs, the scientists report. This implies that intracellular lipid accumulation may exacerbate damaging inflammatory pathways. The findings dovetail with those of a recent study that tied lipid droplet-accumulating microglia (LAM) in the aging hippocampus to neuroinflammation (Aug 2019 news).

Overall, the findings cast PLC2 as a two-faced player in microglia. When triggered via TREM2, this phospholipase facilitates processing of lipids and microglial survival. When tripped off by TLRs, it ramps up potentially damaging pro-inflammatory responses. And when lipids build up, as might occur in the aging brain, they exacerbate the pro-inflammatory pathway, Andreone told Alzforum. He believes the balance between these two PLC2 signaling pathways could dictate whether microglia help or harm.

The findings lend support to a therapeutic strategy of agonizing TREM2 signaling, Lewcock told Alzforum. That the protective PLC2 variant enhances lipid processing in microglia fits with the idea that even people whose TREM2 functions normally could stand to benefit from a boost in this pathway. Activating PLC2 is also a potential strategy, Lewcock said, although it would come with the risk of rousing its pro-inflammatory side. More work is needed to dissect how the PLC2 protective variant influences signaling downstream of TREM2 versus TLRs.

This is a very important paper, wrote Christian Haass at the German Center for Neurodegenerative Diseases in Munich. Haass noted that its findings fit with fresh data from his and other groups, but also cautioned that the molecular signature of a protective subpopulation of microglia needs to be defined in much greater detail (full comment below).

Denali is collaborating with Haass group to develop an activating antibody for TREM2, which will come with a blood-brain barrier transport vehicle to shuttle it into the brain (May 2019 conference news;May 2020 news).AL002, a TREM2-activating antibody developed by Alector and Abbvie, entered early clinical trials last year (see clinicaltrials.gov).Jessica Shugart

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Janus-Faced PCL2? Alzheimer's Risk Protein Toggles TREM2 and TLR Pathways - Alzforum

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