Nature: The strongest AD-related gene, let the brain leak! Scientists studied the brains of 245 volunteers and found for the first time the mechanism by which the blood-brain barrier is broken caused by APOE4

APOE4 is the gene most closely associated with Alzheimer's diseaserecently, a research team led by Professor Berislav VZlokovic of the University of Southern California brought the relationship closer togetherZlokovic's team studied the brains of 245 volunteers and revealed for the first time the mechanism by which APOE4 causes the brain's blood-brain barrier (BBB) to breakThey also found that the breakage caused toxic substances to penetrate the brain's areas responsible for memory and other cognitive functions, and more importantly, the damage to the blood-brain barrier caused by APOE4 was independent of beta-amyloid and tau proteins, which had an independent effect on cognitionthis important study, published in the top journal Nature, gives new insights into Alzheimer's disease and provides new therapeutic targets for scientistsScreenshot of the first page of the paperwe have not written about Alzheimer's research progress for half a yearThis is mainly because the disease is too difficultTake APOE4, which scientists have long found to be linked to Alzheimer's disease, and even carrying a single copy of APOE4 triples the risk of Alzheimer's disease compared to the common APOE3;regret that for so many years, no one has known exactly how APOE4 causes Alzheimer's diseaseblood-brain barrier (pictured: watermark)When we think of Alzheimer's disease, the first thing that comes to mind is beta amyloid and tau protein, but the successive failures of drugs targeting these two proteins, as well as a growing number of other studies, suggest that beta amyloid and tau protein sit not the whole story of Alzheimer's diseasechanges in the blood-brain barrier have gradually attracted scientists' attention in other researchsome studies have shown that changes in the blood-brain barrier are early signs of Alzheimer's disease, and even some studies have found that the extent of damage to the blood-brain barrier is closely related to the severity of Alzheimer's diseaseunfortunately, the exact cause of damage to the blood-brain barrier is also unknown But a growing body of research has found a link between APOE4 and damage to the blood-brain barrier as a pioneer of the hypothesis that damage to the blood-brain barrier leads to cognitive impairment and dementia, Zlokovic intends to explore the relationship between APOE4 and the blood-brain barrier and Alzheimer's disease in the human body, turning the mysterious relationship into causality For this reason, the Zlokovic team recruited 245 volunteers to analyze the permeability of the blood-brain barrier of all participants using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) technology, according to of the University of Southern California they found that the blood-brain barrier of the hippocampus (HC) and hippocampus (PHG) increased in the body of the cognitively normal APOE4 carrier (?3/4 or ?4/4) compared to the cognitively normal APOE3 pure-fit volunteers Moreover, this increase is not related to differences in beta amyloid protein and phosphorylation tau protein in cerebrospinal fluid (CSF) , even a carrier of APOE3 with cognitive impairment, the blood-brain barrier of the hippocampus and the hippocampus did not change much they also observed a phenomenon in which the volume of hippocampus and hippocampus in APOE4 carriers also decreased with cognitive impairment, but a carrier of APOE3 did not exhibit this change even in the control of age, gender, education, levels of beta amyloid and phosphated tau protein in cerebrospinal fluid, and the volume of hippocampus and hippocampus, the damage to the hippocampus and hippocampus blood-back brain barrier of APOE4 carriers remained highly associated with cognitive impairment; they also found that the blood-brain barrier was damaged before brain atrophy and was not associated with systemic vascular risk factors because beta amyloid and tau protein are also associated with vascular abnormalities and damage to the blood-brain barrier, the researchers had to be associated with beta amyloid and tau protein aloof aloof if they were to prove an independent relationship between APOE4 and damage to the blood-brain barrier to figure this out, Zlokovic's team studied 170 volunteers based on positron emission tomography (PET) The final data showed that damage to the blood-back brain barrier of the hippocampus and the hippocampus, which is carried by APOE4 carriers, was not associated with two Risk Factors for Alzheimer's disease, beta amyloid and tau protein at the same time, they also found that the blood-brain barrier damage of APOE4 carriers began in the inner temporal lobe, which is responsible for memory coding and other cognitive functions based on the above studies, researchers can basically determine that APOE4 is a separate line between impaired blood and brain barrierand and cognitive impairment, independent of other factors, especially beta amyloid and tau proteins The seahorse body (HC) and the hippocampus (PHG) so how on earth does APOE4 cause damage to the blood-brain barrier? An in-depth analysis by the Zlokovic team found that levels of soluble platelet-derived growth factor receptor-beta (sPDGFR beta) in the cerebrospinal fluid of APOE4 carriers increased, which was associated with increased permeability of the blood-brain barrier that was returned to the hippocampus and the hippocampus and previous studies have shown that elevated levels of sPDGFR beta mean that cerebral capillary cell damage is associated with damage to the blood-brain barrier and cognitive impairment This process is also associated with the inflammatory procyclic protein A-matrix metalloproteinase 9 (CypA-MMP9) pathway based on this, the researchers focused on the CypA-MMP9 approach researchers analyzed the volunteers' cerebrospinal fluid and found that CypA and MMP9 water in cerebrospinal fluid in APOE4 carriers increased on average compared to APOE3 pure volunteers Based on human-induced pluripotent stem cells, the findings in humans have been confirmed The molecular mechanism of APOE4, which causes damage to the blood-brain barrier
in mouse studies prior to the binding, the researchers believe that APOE4 activates the CypA-MMP9 pathway, which may accelerate the breakdown of the blood-brain barrier and eventually lead to impaired neuronal and synaptic function because previous studies in mice have also found that blocking the CypA-MMP9 pathway in APOE4 mice restores the integrity of the blood-brain barrier CypA inhibitors may have similar effects in APOE4 carriers This may improve cerebrovascular integrity and reduce associated neuronal and synaptic defects, thereby slowing the progression of cognitive impairment in fact, such drugs have been used to treat non-neurotic diseases Scientists studying Alzheimer's disease are expected to do a retrospective analysis to see if there is a link between the use of such drugs and cognitive impairment overall, the study revealed the mechanism by which APOE4 causes the blood-brain barrier to break, and to determine the relationship between this breakage and cognitive impairment However, how the damage to the blood-brain barrier induced by APOE4 causes Alzheimer's disease requires more research to reveal the molecular mechanisms behind it