Inventory: Blockbuster achievements in the field of Alzheimer's disease research in 2021!

Content Source | Bio Valley Alzheimer's disease (AD) is the most common, irreversible and progressive form of dementia
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According to the World Alzheimer's Disease Report 2018, every 3 seconds, one person with dementia develops globally
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At present, there are at least 50 million dementia patients in the world, and it is expected that by 2050, there will be 152 million people, of which about 60%-70% are Alzheimer's disease (AD)
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01Nat Aging: Dysfunctional brain cells may be potential targets for developing new Alzheimer's disease therapies Scientists at the University of Texas at San Antonio and other institutions have identified a rare population of potentially toxic senescent cells in the human brain that could serve as a new target to help develop new Alzheimer's treatments
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Senescent cells are a type of old, weak and sick cells that cannot properly repair themselves and will not die when they should.
On the contrary, they show certain abnormal functions and can release special substances to kill cells.
Kill surrounding healthy cells and trigger inflammation; over time, senescent cells accumulate in the body's tissues, leading to the aging process, neurocognitive decline, and cancer
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In 2018, researchers found that senescent cells would accumulate in a mouse model of Alzheimer's disease, and induce brain cell loss, inflammation and memory damage in mice; when researchers used a therapy to remove senescent cells It inhibits disease progression and cell death
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02Cell: Scientists have successfully designed a new type of muscarinic M1 receptor agonist with potential to treat Alzheimer's disease Esterase to prevent the breakdown of acetylcholine, thereby effectively correcting the defective cholinergic transmission, however, these methods have very limited clinical efficacy; another method is to directly activate the cholinergic receptors responsible for learning and memory, M1-toxic The muscarinic acetylcholine (M1, M1-muscarinic acetylcholine) receptor is the preferred target, but its application has been hampered by adverse side effects
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In a study published in the international journal Cell, scientists from institutions including the University of Glasgow have made breakthrough discoveries from the laboratory to the bedside
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In this study, researchers describe for the first time the process of designing a new type of molecule that selectively targets specific receptor proteins in the brain, in both laboratory preclinical and human clinical studies.
The new approach may show potential in developing new drugs to improve cognitive function in the brains of Alzheimer's patients
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The molecule the researchers focused on selectively targets a receptor molecule in the brain called the M1-muscarinic acetylcholine receptor (M1 receptor), which plays an important role in the body's memory and cognitive functions.
role, and subsequent translational medicine studies tested the hypothesis whether molecules such as these could retain cognitive benefits and lack dose-limiting side effects
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Working closely together, the researchers say that although the M1 receptor is very similar to other types of muscarinic receptors, using a detailed understanding of the 3D structure of the M1 receptor, they are expected to successfully design a highly selective modulator Since, this approach is called structure-based drug design or SBDD
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03Sci Adv: Knockout of the ABI3 gene may increase an individual's risk of Alzheimer's disease doi: 10.
1126/sciadv.
abe3954 As the body's immune cells move throughout the brain, they act as a first line of defense against viruses, toxins and receptors damaged neurons and remove them from the body
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In a study published in the international journal Science Advances, scientists from the Indiana University School of Medicine and other institutions have revealed how immune cells in the brain called microglia interact with recent Alzheimer's disease patients.
In the article, the researchers found that knocking out a gene called ABI3 may significantly increase the accumulation of beta-amyloid plaques in the brain and reduce the levels of microglia around the plaques
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Researchers conducted a human genetics study of more than 85,000 individuals with an ABI3 gene mutation, less than half of whom had Alzheimer's disease, that increases the risk of advanced Alzheimer's disease risk
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The researchers did not investigate the function of the ABI3 gene in the brain or how the gene affects the function of microglia.
In this study, the researchers knocked out the ABI3 gene from a mouse model of Alzheimer's disease and expressed it in the cells.
The gene's function in microglia was examined in culture; in a mouse model, they observed increased levels of plaques and inflammation in the brain, as well as signs of abnormal synaptic function, features that correlate with learning in patients with the disease associated with deficits in memory function
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In addition, the researchers say that knocking out the gene impairs the movement of microglia, which prevent immune cells from getting close to the plaques to try to clear the protein.
Amyloid aggregates and forms plaques, which can disrupt nerve cell connections
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The researchers pointed out that this study provides the first functional evidence that the loss of ABI3 gene function may increase the risk of Alzheimer's disease in individuals by affecting the accumulation of beta amyloid and the development of neuroinflammation
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Study design, data collection flowchart and reasons for missing data
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Image credit: Lu, K.
, et al.
Nat Aging (2021).
doi: 10.
1038/s43587-021-00117-404Nat Aging: The main Alzheimer's disease risk gene APOE4 may be associated with better visual working memory in the elderly population Closely related doi: 10.
1038/s43587-021-00117-4 Although APOE ε4 carriers have a much higher risk of Alzheimer's disease than non-carriers, controversial evidence suggests that APOE ε4 may confer some advantages to carriers , which may explain the survival property of this gene, known as antagonistic pleiotropy
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In a research report published in the international journal Nature Aging, scientists from University College London and other institutions found through research that a gene known to increase the risk of Alzheimer's disease, APOE4, may be better than the elderly.
There is a certain correlation between visual working memory
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"We've long known that the APOE4 risk gene increases the risk of Alzheimer's disease, but what's behind it," said Jonathan Schott, who studied a group of volunteers born the same week in 1946.
Scientists don't know the molecular mechanism
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In this research report, we studied this special group of volunteers and found that carrying the APOE4 gene may be associated with better visual memory in the body, which may provide new clues as to why this gene mutation is so common Understanding why APOE4 leads to better memory may help researchers understand how it increases the risk of Alzheimer's disease
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05Sci Adv: Scientists develop a new blood test that promises reliable diagnosis of Alzheimer's disease doi:10.
1126/sciadv.
abj2137 Quantifies physical differences in blood protein aggregates involved in Alzheimer's disease (AD) Or can provide critical information about the stage of the disease; if a person suspects that they have Alzheimer's disease, they must prepare for long and complex therapeutic steps until the disease becomes clear
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In a research report published in the international journal Science Advances, scientists from the Swiss Federal Institute of Materials Science and Technology and other institutions have developed a new blood detection technology through research, which may be able to use atomic force microscopy (AFM) to detect diseases.
Make a reliable diagnosis
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From the beginning, physicist Peter Nirmalraj wanted to understand the molecular pathological manifestations of Alzheimer's disease through research, so as to develop new diagnostic techniques and therapeutic strategies; then researchers will further analyze the beta amyloid associated with neurodegenerative diseases.
Because of the exact roles played by tau-like and tau proteins, researcher Peter Nirmalraj had to not only detect the presence of the suspect protein, but also determine its variable shapes, forms and levels
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The researchers jointly completed the preliminary study.
In their pilot study, they analyzed blood samples from 50 patients and 16 healthy subjects.
Using AFM technology, the researchers did not know the health of their bodies.
, which analyzed the surface of roughly 1,000 red blood cells in each human body, was the only way to ensure that the interpretation of the data remained objective
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06Nat Med: Inflammation of brain tissue may be a key factor in Alzheimer's disease progression doi: 10.
1038/s41591-021-01456-w There is convincing evidence that microglia activation is involved in Alzheimer's disease The spread of tau tangles in the neocortex in silent disease
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Recently, in a research report entitled "Microglial activation and tau propagate jointly across Braak stages" published in the international journal Nature Medicine, scientists from the University of Pittsburgh School of Medicine and other institutions found through research that neuroinflammation may be a pathological factor in the brain.
A key driver of the proliferation of sexually misfolded proteins that contribute to cognitive impairment in Alzheimer's disease patients
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In this study, the first-ever study in living patients, neuroinflammation, the overactivation of microglia, the brain's resident immune cells, is not just the result of disease progression, but rather It is also a key upstream mechanism that is indispensable for the development of disease
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Tharick Pascoal, MD, said, "Now we're noticing that many Alzheimer's patients go unnoticed so that they don't receive proper care; while this study shows that a combination of targeting reductions in amyloid plaque formation and limiting neuroinflammation Therapy may be more effective than addressing each pathology individually
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Alzheimer's disease is characterized by the accumulation of amyloid plaques (aggregates of proteins that lodge between nerve cells in the brain) and the formation within nerve cells of disordered aggregates of protein fibers called tau tangles
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Although ample evidence has accumulated in laboratory animal studies of nuclei in culture to suggest that activation of microglia drives the spread of tau fibers in Alzheimer's disease, this process has not yet been demonstrated in humans
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Our findings suggest that targeting neuroinflammation may benefit patients with early-stage Alzheimer's disease, and may also help reverse or at least slow the accumulation of pathological tau proteins in the brain and prevent dementia
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Neuroinflammation is lower (red) in younger and older populations than in Alzheimer's disease patients
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Image source: Adapted from Pascoal et al.
, Nature Medicine.
07Nature: Restoring the function of a 'chaperone' protein may prevent the accumulation of toxic plaques in patients with neurodegenerative diseases such as Alzheimer's disease doi: 10.
1038/s41586-021 -03824-5 Protein quality control systems are critical to cellular function and organismal health, most of the currently known protein control systems are multicomponent machines that interact with non-native proteins through ATP-regulated interactions function to function and prevent aggregation of proteins and promote their folding, few systems promote these broadly by different mechanisms, in addition, proteins containing broadly charged poly-Asp/Glu (poly-D/E) regions It is common in the proteome of eukaryotes, but its biochemical activity is unknown to researchers
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In a study published today in the international journal Nature, scientists from the Perelman School of Medicine at the University of Pennsylvania and other institutions have revealed for the first time how restoring levels of the protein DAXX and a large group of similar proteins prevents a known drive to Alzheimer's.
The misfolding of "bad" proteins in Haimer's disease and other neurodegenerative diseases, as well as the specific mutations that cause cancer, may help develop novel targeted strategies to restore biological systems designed to keep key proteins under control and prevent disease.
Function and balance
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In this study, the researchers focused on the DAXX protein, a death domain-related protein and a member of a large family of human proteins, each of which has abnormally high levels of two specific amino acid disabilities, the The various roles played by aspartate and glutamate, known as poly D/E proteins, DAXX and about 50 other poly D/E proteins in cellular processes will be gradually elucidated by researchers over time, But its role in protein quality-control systems—that is, chaperones that direct protein folding—was unexpected by the researchers
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08Nat Biomed Eng: Heavy! Scientists have successfully developed a novel whole-brain genome editing technology that promises to treat Alzheimer's disease doi: 10.
1038/s41551-021-00759-0 Familial Alzheimer's disease is encoded by the amyloid beta precursor protein (app ) and genes encoding presenilin 1 (presenilin 1) and presenilin 2 (presenilin 2) are pathologically characterized by the appearance of extracellular amyloid plaques and intracellular of neurofibrillary tangles
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Recently, a research report entitled "Brain-wide Cas9-mediated cleavage of a causing gene familial Alzheimer's disease alleviates amyloid-related pathologies in mice" was published in the international journal Nature Biomedical Engineering.
Scientists have developed a new technique using whole-brain genome editing technology that may reduce Alzheimer's disease pathology in genetically modified mouse models of Alzheimer's disease.
This advanced technology may It also has great potential to be translated into a novel long-acting strategy for the treatment of Alzheimer's disease patients
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In this study, researchers developed a novel genome editing technology that can not only cross the blood-brain chapter, but also transport optimized genome editing tools throughout the brain, using this newly designed genome editing transport.
This new technology enables efficient whole-brain genome editing via a single non-invasive intravenous injection, and this effectively disrupts the mutation that causes familial Alzheimer's disease in a mouse model of Alzheimer's disease, And can improve Alzheimer's disease symptoms throughout the brain, while also providing ideas for later development of novel therapeutic strategies
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09Nature: Scientists identify special signaling molecules that can help prevent and treat Alzheimer's disease The researchers did not know the effect of glial cells on the accumulation and clearance of beta-amyloid and neurofibrillary tau in the brains of individuals with Alzheimer's disease, although these are therapeutically meaningful interactions
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Recently, in a study titled "Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease" published in the international journal Nature, scientists from Massachusetts General Hospital and Harvard Medical School and other institutions conducted experiments on humans and mice.
Research has identified a specific signaling molecule that may help improve the body's inflammation and immune system function, thereby protecting the body against Alzheimer's disease
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The cognitive decline associated with Alzheimer's disease occurs when neurons begin to die, says researcher Filip Swirski, Ph.
D.
Neuronal death is often caused by an inappropriate immune response and excessive neuroinflammation (or brain inflammation) caused by high levels of beta-amyloid deposits and tau tangles, two major markers of Alzheimer's disease
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Once more and more neurons begin to die, brain cells called microglia and astrocytes (two types of cells that normally help clear the brain of debris) are activated to trigger neuroinflammation, and thus try to protect the brain; these cells have evolved to be programmed to wipe out the rest of the brain's excessive neuronal cell death, which can be caused by an infection and whose spread must be stopped
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In the case of Alzheimer's disease, neuronal cell death triggered by beta amyloid and tau tangles activates this response, and with neuroinflammation, the level of cell death is at least higher than that of beta amyloid.
Like proteins and tau tangles trigger 10-fold higher cell death; in fact, without the induction of neuroinflammation, symptoms of dementia do not occur; the researchers say they know this from the "plastic" brain, in In this case, the individual has a lot of beta-amyloid and tau tangles in the brain, but they die without any symptoms because the body has little or no neuroinflammation
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The researchers point out that beta amyloid is the "prime" that ignites the spread of tau tangles, but it is only neuroinflammation activated by microglia and astrocytes that leads to increasing "forest fires" ", at which point the body loses enough neurons and experiences cognitive decline and dementia
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Properties of pQTLs
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Image credit: Yang, C.
, et al.
Nat Neurosci (2021).
doi: 10.
1038/s41593-021-00886-610Nat Neurosci: Scientists identify novel therapeutic target for Alzheimer's disease doi: 10.
1038/s41593- 021-00886-6Understanding tissue-specific genetic control mechanisms at the protein level is important for uncovering post-transcriptional mechanisms of gene regulation; recently, an article was published in the international journal Nature Neuroscience entitled "Genomic atlas of the proteome from brain, CSF and In the research report "plasma prioritizes proteins implicated in neurological disorders", scientists from Washington University School of Medicine and other institutions have identified potential new therapeutic targets for Alzheimer's disease through research, and also found that current drugs may be effective Attack these targets to treat disease
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These potential targets are defective proteins that cause amyloid accumulation in the brain, which can lead to memory problems and thinking problems that are characteristic of Alzheimer's disease
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Researchers have now identified 15 FDA-approved drugs for other therapeutic purposes, opening the door to clinical trials, perhaps sooner than usual
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In addition, the researchers also obtained seven drugs through experiments, which may be expected to treat the faulty protein associated with Parkinson's disease, including six for stroke and one for ALS
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For decades, scientists have worked hard to develop new Alzheimer's treatments by targeting genes key to the disease process, with little success
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This approach tends to produce dead ends because many genes do not fundamentally alter the proteins that function in the brain
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In this paper, the researchers took a new approach by focusing on proteins in the brain and other tissues
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"We use human samples and the latest technology to better understand the biology of Alzheimer's disease," said researcher Carlos Cruchaga.
"With Alzheimer's disease samples, we can identify novel genes, druggable targets.
And FDA-approved compounds that potentially interact with targets and potentially slow or reverse the progression of Alzheimer's disease
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The scientists focused on protein levels in the brain, cerebrospinal fluid and plasma of Alzheimer's patients and non-patients.
Some of these genes encode proteins associated with the risk of the disease.
When these proteins are identified, the researchers will correlate the findings.
Comparisons were made with several databases of existing drugs affecting these proteins
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These drugs are FDA-approved and all the safety data on these drugs are available, and with an understanding of the safety of these drugs, we can jump straight to clinical trials
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11Mol Psych: Development of a new potential non-invasive technology for the treatment of Alzheimer's disease doi: 10.
1038/s41380-021-01129-7 Progressive physiological aging and impaired and uninducible cognitive performance Long-term potentiation (LTP), which is an electrophysiologically relevant factor in the body's memory
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Recently, in a research report titled "Low-intensity ultrasound restores long-term potentiation and memory in senescent mice through pleiotropic mechanisms including NMDAR signaling" published in the international journal Molecular Psychiatry, scientists from the University of Queensland and other institutions conducted research Ultrasound may be able to overcome some of the adverse effects of aging and dementia without crossing the blood-brain barrier, it has been found
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The researchers point out that low-intensity ultrasound can effectively restore cognitive function in the mouse model without opening its blood-brain barrier
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The results of this study may provide new avenues for the development of new non-invasive technologies, while also helping clinicians to customize individualized therapies to account for disease progression and cognitive decline in each patient's body
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"Historically, we've used ultrasound and small gas-filled bubbles to open the nearly impenetrable blood-brain barrier to deliver therapeutic drugs through the bloodstream into the brain," said researcher Professor Gotz
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In the latest study, the researchers assigned a control group of subjects who received ultrasound without the microbubbles that open the barrier
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The entire research team was amazed at the recovery of cognitive function in the brains of the mouse model; they concluded that this therapeutic ultrasound may be used as a non-invasive technique to enhance cognitive function in the elderly; aging It is directly related to impaired cognitive function, and the plasticity of signaling between neurons induced by the body's learning is also reduced, a process called long-term potentiation
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According to the researchers, the new study aims to use ultrasound to restore LTP and improve spatial learning in aged mice
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12PNAS: Hydrogen sulfide may be effective against Alzheimer's disease In the research report "sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation", scientists from the University of Exeter and other institutions in the United Kingdom found that hydrogen sulfide (hydrogen sulfide) may help effectively prevent the occurrence of Alzheimer's disease
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Hydrogen sulfide, which is characteristically toxic, corrosive and smells like rotten eggs, may soon be improving its "notoriety".
After studying mice, researchers found that hydrogen sulfide's foul odor may The discovery of this biochemical reaction may help researchers develop new drugs to combat neurodegenerative diseases by helping to protect the body's brain cells from developing Alzheimer's disease
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"Our latest results use hydrogen sulfide and other gaseous molecules in cells to firmly link the body's aging, neurodegeneration, and cell signaling," said researcher Bindu Paul.
Under normal circumstances, the body produces small amounts of hydrogen sulfide to help Regulating a variety of systemic functions in the body, from cell metabolism to dilating blood vessels, gas is a major cellular messenger molecule that is especially important for brain health, however, unlike traditional neurotransmitters, gas does not reside in vesicles For storage, it acts through different mechanisms by rapidly promoting cell signaling
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In the case of hydrogen sulfide, it is required to modify the target protein through the action of a chemical sulfide, thereby regulating its activity
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