The Role Of Beta-Secretase And Vascular Pathology In Diseases Related To Cognitive Impairment

Beta-site APP Cleavage Enzyme 1(BACE1)is a rate-limiting enzyme that helps A? production by cleaving Amyloid Precursor Protein(APP).A? aggregates and depositions to form plaques,which is thought to be one of four classical pathological hallmarks of Alzheimer's Disease(AD).Recently,studies have found that the level and enzyme activity of BACE1 are elevated in brain parenchyma,cerebrospinal fluid and plasma from AD patients,which is closely associated with pathological progression,elevated concentration and activity of BACE1 are a vital risk factor of AD.The increase of BACE1 in AD patients could associated with plenty of stress factors,for instance oxidative stress,increased inflammation levels,hypoxia and hyperglycemia and so on.Studies have shown various diseases could increase the risk of cognitive impairment,such as hypertension,cerebrovascualr disease,thyroid disease and diabetes,etc.Cerebrovascular diseases can be divided into large vessel disease(like arteriosclerosis)and small vessel diseases,the latter refers to the injury of vessels which diameter less than 200um.Small vessel diseases can be divided into two kinds:1.aging and hypertension associated Cerebral Small Vascular Diesases(CSVD),which hallmarks include lancues,microbleeds,white matters hyperintensities and enlarged perivascular spaces 2.A? associated Cerevral Amyloid Angiopathy(CAA),which features is the deposition of A? in pial arteries,subcortical vessels and arterioles.CAA is strongly associated with AD.Both CSVD and CAA could lead to the cognitive impairment of patients.Besides,Type-? Diabetes Mellitus(T2DM)is another important risk factor of cognitive impairments.T2DM is a chronic metabolic disease that affects the vast majority of area and populations around the world.Typical characteristics of T2DM include obesity,hyperglycemia,insulin resistance and elevated inflammation levels.T2DM also increases the incidence of many cognitive impairments such as vascular dementia and AD,which lead to cognitive impairments.We noticed that the above diseases which could increase the risk of cognitive impairment are all accompanied with stressors such as inflammation,hypoxia or hyperglycemia,and these foctors may induce increased BACE1 concentration and activity.Hence,we proposed that whether these vascular diseases further promote cognitive impairment via inducing the increase of BACE1 concentration or activity?To answer this question,we recruited patients with AD,CAA,T2DM and T2DM with cognitive impairments,as well as community elderly cohorts,assessed the concentration and activity of plasma BACE1,combined with the pathological features and cognitive status of patients,to explore the association of plasma BACE1 concentration and activity with the pathologies and cognition impairment of patients.The results obtained are as follows:1.BACE1 concentration and activity are associated with cognition:in AD cohort,AD patients had higher plasma BACE1 levels,and BACE1 levels were correlated with cognitive scores;in T2DM cohorts,T2DM and T2DM with cognitive impairment patients had higher plasma BACE1 levels and activities,which were both correlated with cognitive scores;in CAA cohorts,higher BACE1 activities were observed in CAA patients and was correlated with cognitive scores.Besides,BACE1 concentration and activities were elevated in dementia converters;at last,in the community cohorts,after adjusted for age and sex,BACE1 concentration was found to be negatively associated with cognitive scores,A?42/40 ratio was also associated with cognitive scores.These results suggests that BACE1 concentration is associated with cognition,which may via the influence of A? pathology;in other pathologies such as T2DM and CAA,BACE1 activity is also correlated with cognition.2.BACE1 activity is associated with physiology and pathology:?in CAA cohorts,BACE 1 activities was elevated in hypertension and diabetes patients;in community cohorts,after adjusted for age and sex,BACE1 activities were associated with blood pressure,blood glucose and blood lipid levels.?in T2DM cohorts,BACE1 activities was correlated with inflammation levels;in CAA cohorts,BACE1 activities and correlated with white matter hyperintensities;in community cohorts,after adjusted for age and sex,BACE1 activities were associated with arteriosclerosis related markers and vascular inflammation factors.This part indicates that stress factors such as hypertension and hyperglycemia may induce high BACE1 activities,the latter is associated with vascular injury and inflammation levels.Conclusion:The increase of BACE1 levels and activities induced by stressors such as hypertension and hyperglycemia maybe the common mechanism of the elevated cognitive impairment risk of cerebrovascular diseases and T2DM.In this study,we completed the first multicenter plasma BACE1 concentration and activities detection in the world.We used case-control cohorts as discovery group,and used community cohort as validation group.We found that increased plasma BACE1 concentration was associated with cognitive decline,while BACE1 activities was more sensitive to stress such as hypertension and hyperglycemia,and was associated with the increase of vascular inflammation levels.Alzheimer's disease(AD)is the most common neurodegenerative disease in the world and occupies the most important position in all types of dementia.The hallmarks of AD include plaques formed by Amyloid ?(A?)deposition,Neurofibrillary Tangles(NFT)caused by hyperphosphorylated Tau protein,cholinergic synaptic loss and neuronal apoptosis.Except for that,vascular impairment is another hallmark of AD brain.It has been reported that 80%of AD patients have severe vascular pathologies,include small vascular disease,microinfarction,microbleeding and so on.Recent studies have shown that Blood-Brain Barrier(BBB)structural and functional damage exist in AD patients,consider that BBB is responsible for maintaining brain homeostasis,transportation and other important functions,the leakage of BBB will prevent nutrients transported to brain and the harmful biomacromolecule like A?transport out of brain,moreover,the infiltration of other proteins or pathogens even immune cells in plasma into the brain will also lead to neuroinflammation,which promotes the development of AD pathologies.However,the mechanism underneath structural and functional damage of BBB in AD patients is still not clear.Several studies suggested that the abnormally activated inflammation and the A? induced endothelial apoptosis will cause BBB damage.At the same time,abnormal angiogenesis occurred in some central nervous system diseases,the unintegrated structures of tight junctions in novel vessels lead to a compromised BBB,further increase the whole permeability of the vessel network.in the previous study,the cerebral vascular density of AD patients also increased,which suggest that abnormal angiogenesis exists in AD brain.To explore this problem,we combined donated autopsy brain samples from AD and non-AD patients,with recruited cerebrospinal fluid(CSF)samples from the clinical cognitive impairment cohort,to investigate that whether abnormal angiogenesis occurs in AD patients and its possible role in BBB breakdown.The following results were obtained:1.Angiogenesis is present in AD patientsTo explore whether there is pathological angiogenesis in AD patients,we first detect the vascular density in AD patients'brain,and found that the vascular density is increased in AD patients compared with healthy controls(HC).To investigate the mechanism of vascular increasing,we detected angiogenesis markers in brain pyrenchyma,results showed that most angiogenesis markers are increased in AD brain.Consider that most angiogenesis factors will be released to CSF,we measured the expression of growth factors in the CSF in clinical cohort and found that most of the factors were significantly elevated in AD patients.These results showed that indeed hyperangiogenesis is present in AD patients.2.Associations between angiogenesis and AD pathologies.To explore the association between angiogenesis and AD typical pathologies,we divided all patients into two groups according to the CSF p-Tau and A? levels,negative or positive,and compared growth factors between groups.The results showed that most growth factors were elevated in p-Tau positive group but not in A? positive group.Linear regression results showed that more growth factors were associated with p-Tau levels.The above results may imply that A?may not be the major cause of angiogenesis.3.Increased vascular permeability in AD patients.To explore the alters of vascular permeability in AD patients,we first detected the expression of TJs in brain samples,results showed that TJs proteins were decreased in AD brain.Furthermore,immunofluorescence results showed that less TJs expression on endothelial cells.Next,we detected albumin in cohort and calculated a indicator which reflect the permebility of vessel,Albumin Quotient(Qalb).We found that Qalb in AD patients was significantly higher than Healthy Control(HC).Consistant to this result,the Qalb was elevated in the vascular injury group.These results suggested that vascular permeability and vascular pathology is increased in AD patients,and there maybe a correlation between each other.4.Increased vascular permeability is associated with angiogenesis in AD patients.To explore the association between angiogenesis and vascular permeability,we first detected the expression of pro-angiogenesis transcription factors,Slug and Snail in AD brain and found that they were elevated.Then we analyzed the correlation between the Slug/Snail with the expression of TJs,results showed that Slug and Snail were negatively correlated with various TJs,which suggest that angiogenesis stimulated by factors inhibit the expression of TJs.Then we grouped patients according to vascular pathology,and found that two growth factors PAI-1 and P1GF were significantly increased:in vascular injury group.The linear regression results showed that Qalb is associated with three growth factors P1GF,VEGFR2 and IL-8 in all patients.In further patients'classifications,the regression coefficients between Qalb and growth factors were significantly higher in AD patients than HC,and a similar result was observed in patients with worse cognition.The results of this section suggest that increased vascular permeability is associated with angiogenesis and is more evident in AD patients and cognitive impairment patients.Conclusion:Abnormal angiogenesis was present in AD patients.In AD brain,abnormal expressed angiogenesis factors promote vascular regeneration,and up-regulated the expression of Slug and Snail,which inhibit the TJs expression.These results lead to the loss of TJs structures between endothelials,and facilitate BBB breakdown.The data from clinical cohort also showed that angiogenesis factors are associated with BBB permeability.Hence,abnormal angiogenesis may be an excessive mechanism of the increase of BBB permeability in AD patients.