APP

Familial Alzheimer's disease can be transferred via bone marrow transplant, researchers show. When the team transplanted bone marrow stem cells from mice carrying a hereditary version of Alzheimer's disease into normal lab mice, the recipients developed Alzheimer's disease -- and at an accelerated rate. Familial Alzheimer's disease can be transferred via bone marrow transplant, researchers show March 28 in the journal Stem Cell Reports. When the team transplanted bone marrow stem cells from mice carrying a hereditary version of Alzheimer's disease into normal lab mice, the recipients developed Alzheimer's disease -- and at an accelerated rate. The study highlights the role of amyloid that originates outside of the brain in the development of Alzheimer's disease, which changes the paradigm of Alzheimer's from being a disease that is exclusively produced in the brain to a more systemic disease. Based on their findings, the researchers say that donors of blood, tissue, organ, and stem cells should be screened for Alzheimer's disease to prevent its inadvertent transfer during blood product transfusions and cellular therapies. "This supports the idea that Alzheimer's is a systemic disease where amyloids that are expressed outside of the brain contribute to central nervous system pathology," says senior author and immunologist Wilfred Jefferies, of the University of British Columbia. "As we continue to explore this mechanism, Alzheimer's disease may be the tip of the iceberg and we need to have far better controls and screening of the donors used in blood, organ and tissue transplants as well as in the transfers of human derived stem cells or blood products." To test whether a peripheral source of amyloid could contribute to the development of Alzheimer's in the brain, the researchers transplanted bone marrow containing stem cells from mice carrying a familial version of the disease -- a variant of the human amyloid precursor protein (APP) gene, which, when cleaved, misfolded and aggregated, forms the amyloid plaques that are a hallmark of Alzheimer's disease. They performed transplants into two different strains of recipient mice: APP-knockout mice that lacked an APP gene altogether, and mice that carried a normal APP gene. In this model of heritable Alzheimer's disease, mice usually begin developing plaques at 9 to 10 months of age, and behavioral signs of cognitive decline begin to appear at 11 to 12 months of age. Surprisingly, the transplant recipients began showing symptoms of cognitive decline much earlier -- at 6 months post-transplant for the APP-knockout mice and at 9 months for the "normal" mice. "The fact that we could see significant behavioral differences and cognitive decline in the APP-knockouts at 6 months was surprising but also intriguing because it just showed the appearance of the disease that was being accelerated after being transferred," says first author Chaahat Singh of the University of British Columbia. In mice, signs of cognitive decline present as an absence of normal fear and a loss of short and long-term memory. Both groups of recipient mice also showed clear molecular and cellular hallmarks of Alzheimer's disease, including leaky blood-brain barriers and buildup of amyloid in the brain. Observing the transfer of disease in APP-knockout mice that lacked an APP gene altogether, the team concluded that the mutated gene in the donor cells can cause the disease and observing that recipient animals that carried a normal APP gene are susceptible to the disease suggests that the disease can be transferred to health individuals. Because the transplanted stem cells were hematopoietic cells, meaning that they could develop into blood and immune cells but not neurons, the researchers' demonstration of amyloid in the brains of APP knockout mice shows definitively that Alzheimer's disease can result from amyloid that is produced outside of the central nervous system. Finally the source of the disease in mice is a human APP gene demonstrating the mutated human gene can transfer the disease in a different species. In future studies, the researchers plan to test whether transplanting tissues from normal mice to mice with familial Alzheimer's could mitigate the disease and to test whether the disease is also transferable via other types of transplants or transfusions and to expand the investigation of the transfer of disease between species. "In this study, we examined bone marrow and stem cells transplantation. However, next it will be important to examine if inadvertent transmission of disease takes place during the application of other forms of cellular therapies, as well as to directly examine the transfer of disease from contaminated sources, independent from cellular mechanisms," says Jefferies. This research was supported by the Canadian Institutes of Health Research, the W. Garfield Weston Foundation/Weston Brain Institute, the Centre for Blood Research, the University of British Columbia, the Austrian Academy of Science, and the Sullivan Urology Foundation at Vancouver General Hospital.

Using novel genetic and genomic tools, researchers have shed light on the role of immune cells called macrophages in lipid-rich tissues like the brain, advancing our understanding of Alzheimer's and other diseases. The study represents a step forward in understanding immune cell regulation and its impact on disease progression. Using novel genetic and genomic tools, researchers at the Icahn School of Medicine at Mount Sinai have shed light on the role of immune cells called macrophages in lipid-rich tissues like the brain, advancing our understanding of Alzheimer's and other diseases. The study, published in the March 6 online issue of Nature Communications, represents a step forward in understanding immune cell regulation and its impact on disease progression. The researchers initially studied genes controlling macrophages, also referred to as microglia when they are in the brain, particularly in response to damage of fatty tissues like the brain. Disease-associated microglia/macrophages are thought to be protective, as they participate in removing lipid-rich waste derived from tissue damage. Therefore, researchers wanted to find factors that promote the "garbage removal" activity of these cells. They identified two influential genes, BHLHE40 and BHLHE41, and used advanced gene editing technology (CRISPR-Cas9) to deactivate them in lab-grown cells. These cells were then transformed into microglia. The resulting microglia lacking BHLHE40 and BHLHE41 resembled disease-associated microglia observed in Alzheimer's disease, showing improved ability to clear cholesterol-rich waste. Confirmation came from experiments on cultured human peripheral macrophages and microglia from mice lacking these genes. "Through our analysis of single-cell datasets from multiple organs, we've uncovered pivotal regulators of immune cell function essential for tissue health," says senior study author Alison M. Goate, DPhil, the Jean C. and James W. Crystal Professor and Chair of Genetics and Genomic Sciences at Icahn Mount Sinai. "Our use of advanced models has further validated the critical role played by transcription factors BHLHE40 and BHLHE41, proteins that regulate gene expression by binding to specific DNA sequences, in controlling immune cell responses, presenting potential targets for therapeutic intervention." Next, the researchers will investigate whether microglia without BHLHE40 and BHLHE41 can help clear away harmful amyloid proteins. In one experiment, the investigators will grow brain cells such as neurons and astrocytes that have harmful Alzheimer's mutations in a dish and test whether immune cells without BHLHE40 and 41 influence beta-amyloid levels, neurodegeneration, and cytokine response (neuroinflammation). In another, they will inject the immune cells with and without BHLHE40 and 41 into a mouse model of Alzheimer's to see how they affect the development of Alzheimer's-like plaques. "We want to see how these cells, particularly those without the two genes, impact Alzheimer's-related phenotypes in both dish and mouse models. We predict that in mice, microglia without BHLHE40 and 41 will clear away beta-amyloid plaques more effectively than control microglia that have normal levels of BHLHE40 and 41. Also, we're exploring how lack of these genes in the brain immune cells affect other types of cells in the brain such as neurons and astrocytes," says Dr. Goate. The paper is titled "BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues." The remaining authors of the paper, all with Icahn Mount Sinai except where indicated, are: Anna Podlesny-Drabiniok, PhD; Gloriia Novikova, PhD; Yiyuan Liu, PhD; Josefine Dunst, PhD (Anocca in Sweden); Rose Temizer, PhD candidate (National Institute of Mental Health); Samuele Marro, PhD; Taras Kreslavskiy, PhD (Karolinska Institute); and Edoardo Marcora, PhD. The study was made possible by funding from various sources, including NIH grants (RF1AG054011, U01AG058635, R56AG081417, U01AG066757, NHLBI R01HL153712, S10OD026880 and S10OD030463) and support from The JPB Foundation and BrightFocus Foundation (A2021014F), the New York State Department of Health stem cell biology fellowship (NYSTEM- C32561GG), America Heart Association (20SFRN35210252), and Graduate Women in Science Fellowship.

MIT researchers say a noninvasive treatment could stimulate gamma frequency brain waves and potentially help treat chemo brain. In a study of mice, the researchers delivered daily exposure to light and sound with a frequency of 40 hertz. They found that this protected brain cells from chemotherapy-induced damage — also called chemo brain. The treatment also helped to prevent memory loss and the impairment of other cognitive functions. Originally developed as a way to treat Alzheimer’s disease, the team at MIT says this treatment could have more widespread effects capable of helping with a range of neurological disorders. “The treatment can reduce DNA damage, reduce inflammation, and increase the number of oligodendrocytes, which are the cells that produce myelin surrounding the axons,” Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the Picower Professor in the MIT Department of Brain and Cognitive Sciences, said in a post on the MIT website. “We also found that this treatment improved learning and memory, and enhanced executive function in the animals.” Tsai serves as the senior author of the new study, which appeared in Science Translational Medicine. The paper’s lead author is TaeHyun Kim, an MIT postdoc. The mice studies run by Tsai and her team found that exposure to light flickering at 40 hertz or sounds with a pitch of 40 hertz and stimulate gamma waves in the brain. This produces protective effects, including the prevention of the rotation of amyloid beta plaques. Using light and sound together provides even more significant protection, MIT says. Phase 1 clinical trial results from humans with early-stage Alzheimer’s also found the treatment safe with some neurological and behavioral benefits. In the new study, the MIT team looked into whether the treatment could counteract the cognitive effects of chemotherapy treatment. Research showed that chemotherapy drugs can induce inflammation on the brain and other detrimental effects, like the loss of white matter. They also promote the loss of myelin, MIT says, and many of these effects are seen in Alzheimer’s. “Chemo brain caught our attention because it is extremely common, and there is quite a lot of research on what the brain is like following chemotherapy treatment,” Tsai said. “From our previous work, we know that this gamma sensory stimulation has anti-inflammatory effects, so we decided to use the chemo brain model to test whether sensory gamma stimulation can be beneficial.” The researchers used mice given cisplatin, a chemotherapy drug commonly used to treat testicular, ovarian, and other cancers, over five days. They then took the mice off the drug for five days, then put them on again for five days. One group received chemotherapy only, while another received 40-hertz light and sound therapy every day. After three weeks, mice that received cisplatin but not gamma therapy displayed many expected effects of chemotherapy. That included brain volume shrinkage, DNA damage, demyelination and inflammation. Those mice also had reduced populations of oligodendrocytes, the brain cells responsible for producing myelin. On the other hand, mice that received gamma therapy with cisplatin showed significant reductions in all of these symptoms. Gamma therapy also had beneficial effects on behavior, MIT says. Mice that received this therapy performed “much better” on tests designed to measure memory and executive function. Using single-cell RNA sequencing, the researchers looked at the gene expression changes that occurred in mice that received the gamma treatment. They saw that, in those mice, inflammation-linked genes and genes that trigger cell death were suppressed. This proved especially true in oligodendrocytes. Mice that received gamma treatment with cisplatin still displayed some beneficial effects visible up to four months later. However, they found that the gamma treatment was much less effective when started three months after chemotherapy ended. They also saw that gamma treatment improved signs of chemo brain in mice that received methotrexate, a different chemotherapy drug. This drug often treats breast, lung and other kinds of cancer. Tsai’s lab now plans to test gamma treatment in mouse models of other neurological disease, including Parkinson’s and multiple sclerosis. Cognito Therapeutics, founded by Tsai and MIT Professor Edward Boyden, completed a Phase 2 trial of gamma therapy in Alzheimer’s patients and plans for a Phase 3 trial this year. “My lab’s major focus now, in terms of clinical application, is Alzheimer’s; but hopefully we can test this approach for a few other indications, too,” Tsai said.