| Background and objectiveAlzheimer's disease (AD),the most commen neurodegenerative disease, characterized by progressive loss of memory and cognitive among older adults. The deposition of amyloid-beta (A?) in the extracellular space of the cerebral cortex and walls of cerebral blood vessels is one of the major histopathological hallmarks of AD. Ap is generated by the proteolyticcleavage of the A? precursor protein (A?PP), an integral type I membrane protein expressed in many tissues and concentrated in the synapses of neurons. Besides the brain, A?is also produced in peripheral tissues which can contribute to blood A?. Platelets are the first peripheral source of A?PP protein and can generate A? in a mechanism similar to neurons.Other possible sources for the production of peripheral A? are skin fibroblasts, skeletal muscles and cerebrovascular smooth muscle cells. It has been generally accepted that Ap deposited in the brain originates from the brain tissue itself. However, circulating A? is capable of crossing the blood-brain barrier (BBB). Whether A? derived from the periphery contributes to AD type pathologies remains largely unknown. In the present study, we aimed to determine whether periphral A? could contribute to AD type pathologies in the brain of non-transgenic mice. By using a model of parabiosis between APPswe/PS1dE9 AD model mice and their wild type (Wt) littermates, we demonstrated that peripheral A? itself could enter brain and form AD type pathologies in Wt mice, supporting the notion that Ap is transmissible between individuals and that the dysfunctions of A? metabolism might be a systemic problemin AD, which might be a systemic disease. So we futher investigated the association between blood AD biomarkers and infectious burden, chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSAS),aiming to understand AD pathogenesis from system perspective.Materials and methodsStudy 1: Pereripheral amyloid-beta induces Alzheimer's pathologies in wild type mice1. Parabiosis. APPswe/PS1dE9 Tg mice were obtained from Jackson Laboratory. Female wild type and Tg mice were used in the present study. Each pair of miceat 9 months of age were placed together in a cage for one month to allow the mice to adapt to each other. Female Tg mice and their age- and weight-matched female Wt littermates were selected for parabiosis including the parabiosis from 10-months of age to 12-months of age, the parabiosis from 10-months of age to 14-months of age, from 10-months of age to 18-months of age and from 10-months of age to 22-months of age (n = 6 per group). The age-matched female Wt mice (n=6 per group) without parabiosis were used in parallel as controls. Animals were anesthetized and placed in a parallel orientation.A left lateral incision was made on one mouse while a right one was made on the partner mouse, extending from the base of the ear toward the hip.The incision included skin and muscle along thorax and abdomen. The opposing muscle layers of the two mice were joined with 5-0 silk sutures. The scapula of each mouse was fixed together with 4-0 silk sutures. The corresponding dorsal and ventral skin was sutured with 4-0 silk. After the surgery,the parabiotic mice were allowed to recover in a warm and clean environment before being transferred into the husbandry area. Prophylactic antibiotic treatment (enrofloxacin, 5 mg/kg) was started one day prior to the surgery and continued for one week. All animals received analgesic/anti-inflammatory treatment (acetylsalicylic acid 5 mg/kg) for two weeks.2. Tissue sampling. All mice were killed humanely by overdosing with 6% chloral hydrate (6 ml/kg). Blood was sampled from the right atrium of the heart. Then perfused with 0.1% NaNO2 in normal saline, and the brains were sampled and weighed. Each right hemisphere peranimal was fixed in 4% paraformaldehyde for histological analysis, andthe left hemisphere was frozen at -80? for biochemical analysis.3. AD type pathologies. Coronal sections of the brain were cut and stored at 4? as previously described. A series of five equally spaced tissue sections (?1.3 mm apart) spanning the entire brain were used for each type of staining. To determine whether peripheral A?entered and deposited in the brain of Wt mice, brain sections were selected and stained with 6E10, 4G8, Congo red and thioflavine-S as previous described. Cerebral amyloid angiopathy(CAA) was also detected by using 1A4 and 6E10 double immunofluorescence. For the intraneuronal A? staining, brain sections were stained by double immunohistofluorescence for DAPI and 6E10, as well as DAPI and A11. A series of sections was also selected and stained by double immunohistofluorescence for E10 and microglia,as well as 6E10 and astrocyte.For the microhemorrhage staining, brain sections were stained for hemosiderin with 2%potassium ferrocyanide in 2% hydrochloric acid for 15 min,followed by a counter staining with 1% Neutral Red solution for 10 min at room temperature. Microhemorrhage profiles were counted under microscopy, and the average number of hemosiderin deposits per section was calculated. Immunostaining with antibodies against either p75 neurotrophin receptor(p75NTR) or neurofilament 200 (NF200) was used to evaluate the neuronalaxons damage.Quantification was conducted by an investigator who was blinded to the group information of the samples.4. ELISA assays. Frozen brain was extracted for Ap analysis from the left hemisphere using a two-step extraction method. First, the brain was homogenized and sonicated in RIPA buffer. Homogenates were centrifuged at 100,000 x g 4? for 60 min, and the supernatant was collected and represented the "soluble" extract. The resulting pellet was then homogenized in 200 ?l of 70% formicacid (FA) and centrifuged again at 100,000 x g 4? for 60 min. The supernatant was collected and neutralized 1:20 with 1M Tris-HCI (PH =11), representing the"insoluble" extract. Levels of A?40 and A?42 were measured using ELISA kits.Concentrations of proinflammatory cytokines including IL-1?, IL-6, IFN-yand TNF-a in brain extracts were measured with ELISA according to the manufacturer's instructions. PierceTM?BCA protein assay kit was used to determine the total protein concentrations. The obtained levels of A? and proinflammatory cytokines were normalized to the protein concentration of the samples.5. Western blot. Proteins in the animal brain homogenate were extracted with RIPA buffer. Samples were loaded on SDS-PAGE (4-10-15% acrylamide) gels. Separated proteins were transferred to nitrocellulose membranes. The blots were probed with anti-A?, pS199,pS396, PSD93, PSD95, VAMP1, synaptophysin, LRP-1 and RAGE antibodies. The membranes were incubated with IRDye 800CW secondary antibodies (Li-COR) and scanned using the Odyssey fluorescent scanner. The band density was normalized to ?-actin when analyzing.Study 2: The association between infectious burden and Alzheimer's diseaseOne hundred and twenty-eight consecutive AD patients were recruited from Chongqing Daping Hospital from January 2012 to June 2014. 135 age and gender-matched controls with normal cognition were randomly recruited from health examination center of the hospitals during the same time. Antibody titers to common infectious pathogens including Cytomegalovirus (CMV), Herpes simplex virus type-1 (HSV-1), Borrelia burgdorferi (B.burgdorferi), Chlamydophila pneumoniae (C. pneumoniae) and Helicobacter pylori (H. pylori)were measured by ELISA. Infectious burden was defined as a composite serologic measure of exposure to common pathogens. Serum A?40, A?42 and inflammatory cytokines (i.e.,IFN-?,TNF-?, IL-1? and IL-6) were measured by ELISA kits. The association between infectious burden and the risk of AD was analyzed by unconditional logistic regression analysis,adjusted by demographic data and all comorbidities. The differences of serum A? levels and inflammatory cytokines between healthy controls and AD patients were compared by two-independent t test or one-way ANOVA.Study 3: The association between obstructive sleep apnea syndrome and blood AD biomarkersA total of 94 subjects with possible OS AS were recruited from the sleep center of the Daping Hospital from September to December of 2014. Among these patients, 45 were ultimately diagnosed with OSAS. Forty-nine age- and gender-matched subjects diagnosed with simple snoring and not OSAS were included as the control group. Participants with abnormal cognition according to the Chinese version of the MMSE were excluded. The diagnosis of OSAS was based on the daytime and nocturnal symptoms and nighttime polysomnography (PSG). SerumA?40, A?42, total tau and phosphorylated tau 181 (P-tau 181)levels were measured using ELISA kits.Study 4: The association between chronic obstructive pulmonary disease and blood AD biomarkersIn all, 77 consecutive COPD patients were recruited from Chongqing Daping Hospital from May to September in 2014, and 45 age- and gender- matched normal controls (NC) were randomly recruited from the health examination center of the same hospital in the same period.Cognitively normal COPD patients were determined by the normal scores of the Chinese version of mini-mental state examination (MMSE). Pulmonary function tests were performed to assess the pulmonary function and determine the degree of lung damage. Serum C-reactive protein (CRP) and IL-6 levels were measured using immunoturbidimetric assays. Serum procalcitonin (PCT) levels were measured using enzyme-linked fluorescent assay. Serum A?40 and A?42 levels were determined using human A?ELISA kits.ResultsStudy 1: Pereripheral amyloid-beta induces Alzheimer's pathologies in wild type mice1. Brain A? levels in wild type mice were increased in a time-dependent manner after parabiosis. Parabiosis was performed at 10 months of age and samples were collected for analysis at the age of 12 months [pa(10-12mon)Wt], 14 months [pa(10-14mon)Wt], 18 months [pa(10-18mon)Wt] and 22 months [pa(10-22mon)Wt] respectively. After parabiosis,the blood A?40 and A?42 levels of the parabiotic wild type mice (paWt) were comparable to that of the parabiotic Tg mice (paTg), and were significantly higher than that of the control wild type mice, indicating that A? from the paTg mice entered the circulation of the paWt mice. A? levels in brain homogenates of paWt mice was first measured using western blot.Brain A? could be detected in parabiotic Wt mice after parabiosis for more than 4 months,and it was gradually increased with the parabiotic time. ELISA tests also showed a significant time-dependent increase of A? levels in both soluble and insoluble brain extracts of paWt mice.2. Cerebral ?-amyloidosisin parabiotic wild type mice. Brain sections of pa(10-12mon)Wt, pa(10-14mon)Wt, pa(10-18mon)Wt and pa(10-22mon)Wt mice were then stained with 6E10, 4G8, Congo red and thioflavine-S. No A? deposits were observed in the brains of pa(10-12mon)Wt, pa(10-14mon)Wt or pa(10-18mon)Wt mice. In pa(10-22mon)Wt mice, A?deposits could be detected in the cerebral blood vessels characterized as cerebral amyloid angiopathy(CAA) and brain parenchyma. Significantly, intraneuronal A? was found in brain neocortex in pa(10-22mon)Wt mice, indicating that peripheral A? entered and accumulated in neurons.3. Other AD type pathologies in the brain of parabiotic wild type mice. Next we investigated whether other AD pathologies could be present in the brain of paWt mice after one year parabiosis with Tg AD mice. p75NTR is localized in the cholinergic neurons. A previous study showed that A? causes p75NTR-positive fibers and degenerative neurites in the neocortex. The p75NTR labeled degenerative neurites were observed in brain neocortex of pa(10-22mon)Wt mice. NF200 immunohistochemistry staining showed that the number of NF200 positive nerve fibers was significantly reduced whereas more NF200 protein accumulated as aggregates in neuronal somas. Furthermore, compared to control Wt mice,neuroinflammation was increased in the brain of pa(10-22mon)Wt mice, as reflected by the GFAP-positive reactive astrocytes and CD45-positive reactive microglia near A?-deposits,and increased levels of proinflammatory cytokines including TNF-?, IFN-?, IL-1? and IL-6.Then we detected cerebral microhemorrhage in brain sections stained with Prussian blue staining. Notably, the number of microhemorrhage profiles was significantly increased in pa(10-22mon)Wt mice.Study 2: The association between infectious burden and Alzheimer's disease0 to 2, 3, and 4 to 5 seropositivities toward these pathogens were found in 44%,40% and 16% healthy controls, but in 20%, 44% and 36% AD patients, respectively. Infectious burden,bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. MMSE scores were negatively correlated with infectious burden in all cases. Serum A?40, A?42 levels and inflammatory cytokines (i.e., IFN-?, TNF-?, IL-1? and IL-6) in individuals exposed to 4 to 5 infectious pathogens were significantly higher than that exposed to 0 to 2 or 3 pathogens.Study 3: The association between obstructive sleep apnea syndrome and blood AD biomarkersCompared with the controls, the OSAS patients exhibited significantly higher serum A?40, A?42 and total A? levels, and each of these levels was correlated with the apnoea-hypopnoea index, the oxygen desaturation index, and the mean and lowest oxyhaemoglobin saturations in the OSAS patients. Moreover, the OSAS patients exhibited strikingly higher serum P-tau 181 levels, and these levels were positively correlated with serum A? levels.Study 4: The association between chronic obstructive pulmonary disease and blood AD biomarkersSignificantly increased levels of serum A?40, A?42 and total A? levels were found in patients with COPD in comparison with normal controls. In COPD patients, serum A? levels were higher in subjects with serum CRP, IL-6 and PCT upper the limit of normal. Moreover,serum A? levels were dramatically higher in COPD patients with worse pulmonary function.DiscussionStudy 1: Pereripheral amyloid-beta induces Alzheimer's pathologies in wild type mice In the present study,the parabiosis model was used to investigate whether peripheral A?can enterand deposit in the brain of Wt mice. Parabiosis provides paWt mice with a resource of peripheral A? from blood of Tg AD model mice. As such it is a reliable model to investigate whether peripheral AP can enter and deposit in the brain. After parabiosis for 12 months,CAA and small A? plaques were observed in Wt mice. In addition,intraneuronal A?was found in paWt mice, further suggesting that peripheral A? can enter brain parenchyma.More importantly, neurodegeneration, neuroinflammation and microhemorrhage were obvious in paWt mice,indicating that blood A? itself can not only enter the brain but also cause multiple associated pathologies. This study for the first time reveals that AD type pathologies could be induced ina host that never generates human A? A previous study demonstrated that high levels of circulating A? peptide did not cause cerebral ?-amyloidosis in APP-C99 transgenic mice. The different results probably are due to the different genetic background of the mouse and different AD model which express C99 peptide, whereas our mice were only exposed to human A? without expression of human A?PP.A? cascade hypothesis is now being questioned because clinical trials targeting A?repetitively failed. AD transgenic mice overexpressing A?PP display neuronal loss and cognitive decline, and transgenic expression of APP intracellular domain (AICD) can also cause neurodegeneration, suggesting that other domains of APP may participate in AD pathogenesis. However, the expression level of A?PP in most AD patients (sporadic AD) is similar to that observed in normal people. It appears that the decrease of A? clearance is the main cause of excessive A? accumulation in sporadic AD. In this study, Wt mice without human A?PP expression developed AD type pathologies after a constant exposure of exogenous A? for one year,providing evidence that A? is the core pathogenic substance of AD.Brain AP plaques and CAA can be prematurely induced in Tg mice injected by intracerebral or intraperitoneally routes with A?-rich brain homogenates from AD patients or aged Tg mice, suggesting a prion-like seeding activity of A?. The A? deposition induced by exogenous A? is dependent on both the time and the concentration of A? in the brain extracts. Furthermore, this A? deposition originated from the host itself and not the injected homogenates containing A?. In the above studies,brain A? pathology was observed in Tg mice expressing mutant human A?PP, while it was refractory to be induced in the Wt mice and rats. Recent studies found that A? pathologies were found in the brain of patients with iatrogenic Creutzfeldt-Jacob disease (CJD) who had received A?-contaminated pituitary hormone or underwent dural grafting when young, implying that peripheral Ap may act as seeds and transmit from human to human. However, whether peripheral A? itself can enter and accumulate in the brain remains unclear. In our study,we provide direct evidence that peripheral A? can form AD pathologies in the brain. We also for the first time provided evidence that AD type pathologies from individuals of AD (Tg mice) can be transferred to normal individuals (Wt mice) which do not express human A?PP,implying that A? itself is transmissible to form deposition and induce AD type pathologies. Our study may reveal a novel mechanism of peripheral A? pathogenesis which is different from that of the "seeds"hypothesis. This novel way of induction of AD pathologies requires a constant supply of peripheral A? for at least 12 months because a shorter period of exposure of A? did not cause any pathological changes. These results indicate that AD pathologies in Wt mice require two critical factors, ie, human A? and constant exposure of human Ap for a long period of time. This is relevant to human sporadic AD which develop AD pathologies over many years.A? is generated by the proteolytic processing of the A?PP, which is expressed in both brain and peripheral tissues. Blood A? is derived from different sources including brain and peripheral organs and tissues. Platelets are reported as the first peripheral source of A?PP and A? after the brain, and platelet membrane ?-secretase activity is increased by 24% in patients with mild cognitive decline (MCI) and by 17% in those with AD. An earlier study found a significant increase of A? secretion in skin fibroblasts from AD patients. The temporalis muscles of AD patients were also reported to contain significantly higher A? levels compared to the normal group. Epidemiological studies showed that patients with osteoporosis have an increased risk of developing AD,and osteocytes can produce A? which was elevated in osteoporotic bone tissues osteocytes. A? levels were also detected in human liver, aorta,and leptomeningeal arteries. Therefore, the dysfunctions of A?PP metabolism might be a systemic problemin AD.According to A? cascade hypothesis, the imbalance of Ap production and clearance in brain causes AP deposition and drives AD pathogenesis. However, the potential significance of circulating A? on AD pathology remains largely unknown. In our study, we observed vascular A?deposition, small A? plaques, and intraneuronal A? accumulation in parabiotic Wt mice. This study suggests that peripheral A? contributes to brain A? pathology,shedding new insight on the understanding of AD pathogenesis and suggesting that systemic A? is also critically involved in AD. Indeed, recent findings reveal that peripheral organs and tissues are capable of clearing A?, and systematic diseases is closely correlated with AD risk or A?metabolism. Blood A? levels are significantly higher in patients with chronic kidney disease and liver failure. Thus the dysfunction of peripheral A? clearance and/or over-production of A? could lead to the accumulation of A? in blood, which might contribute to AD development.As separation of the parabionts causes substantial lesions and stress to the animals,like other studies using the parabiosis model, behavioral tests were not possible to examine whether cognition decline appears in parabiotic Wt mice. However, we observed obvious A?pathologies, neuroinflammation, and neurodegeneration in parabiotic Wt mice, which would likely support cognitive decline. In conclusion, our study reveals thatperipheral A?contributes to AD type pathology, suggesting that A? is transmissible between individuals and shedding new insight into the understanding of AD pathogenesis.Study 2: The association between infectious burden and Alzheimer's diseaseThis study shifts focus from one specific infection to IB and assumes that each pathogen works together to contribute to cognitive decline, providing the first evidence that accumulative infections are associated with AD.The mechanism for the association between IB and AD observed in the present study remains uncertain. One explanation is that individuals with AD might be more vulnerable to infectious pathogens in consideration of their cognitive and motor deficits. Another explanation is that past or chronic infection may promote the progression of AD, as past exposure to several vaccines may protect against subsequent development of AD. It has been known that chronic infections caused by pathogens analyzed in the present study can lead to cardio-cerebral vascular disorders, and these diseases promote the development of AD. Thus IB may contribute to the pathogenesis of AD via cardiovascular and cerebrovascular diseases.Inflammation is strongly associated with neurodegeneration and cognitive decline.Inflammation in brain has been also thought to play a vital role in both vascular dementia and AD. In this study, subjects with higher IB had more inflammatory markers in serum,suggesting that IB may convey increased risk of AD through its association with inflammation.The finding that subjects with higher IB contained more Ap in serum help us better understand the association of IB and AD. An early study showed that HSV-1 infection increased A? production by up regulation of P- and y- secretase levels in cell cultures. Besides,Ap has been shown to be a pore-forming antimicrobial peptide. Thus IB elevation may directly increase Ap levels and then promotes the development of AD. In recent years, many researchers proposed that AD might be an autoimmune disorder, based on the prevalent existence of autoantibodies to brain antigens (e.g., A?) in the peripheral blood. But the source of these autoantibodies is not clear. Homology search against infectious agents revealed that these common pathogens express proteins with marked homology (pentapeptides or more) to A? and A?PP. We hypothesize that infection may trigger autoantibodies that could cross-react with membrane-bound A?PP, cause synaptic and neuronal dysfunction, and subsequent cognitive decline.Our study extends the previous findings that IB is associated with AD and provides evidence supporting the hypothesis of an infectious etiology of this devastating disorder.Early vaccination and pathogen elimination may become an important approach for AD prevention and treatment.Study 3: The association between obstructive sleep apnea syndrome and blood AD biomarkersTo our knowledge, this is the first study to address the serum A? and P-tau levels of patients with OS AS. These findings suggest that hypoxia might facilitate AD type pathogenesis in humans.The causal relationship between OSAS and A? levels requires further investigation.Previous studies have indicated that OSAS is associated with increased risks of dementia and AD. In OSAS, in addition to nocturnal intermittent hypoxia, poor sleep quality is also an aspect of the pathophysiology of the disease thatcan impair cerebral metabolism, glucose transport and blood-brain barrier functions and even influence A? metabolism in the brain.The correlations of serum A? and P-tau 181 levels with the severity of OSAS and the extent of nocturnal hypoxia remained after adjusting for the confounders of total sleep time, sleep efficiency and sleep stages, suggesting that hypoxia might increase the levels of A? and P-tau in OSAS patients.Under conditions of chronic hypoxia,the expression of ADAM 10, which is a candidate protein for a-secretase, is decreased in neuronal cells. Additionally, hypoxia increases the BACE-1 level and the enzymatic activity of this protein by enhancing hypoxia-inducible factor l? (HIF-1-?) expression, which results in increased A? generation in a mouse model of hypoxia. On the other hand, hypoxia down-regulates the zinc metalloproteinase neprilysin(NEP), one of the most prominent A? degrading enzymes. These studiessupport the perspective that hypoxia may increase A? levels by up-regulating its production and down-regulating its degradation in the brain. AP levels in the brain and serum form a dynamic equilibrium. The transport of A? from the brain into the peripheral blood has been demonstrated in both animal models and humans, and higher serum A? levels might represent higher A? burden in the brain. In this regard, our results are consistent with those of previous animal studies that have found that hypoxia is associated with increased A? production in the brain. On another hand, increased serum A? levels might also originate from the peripheral organs and tissues that express A?PP and BACE-1, in response to hypoxia in patients with OSAS. It has been suggested that A? originating from the periphery can enter the brain and accelerate AD pathogenesis. Serum phosphorylated tau protein has been suggested to be a biochemical marker of neuronal injury in the brain. In the present study, we found that serum P-tau 181 levels were increased and correlated with the A? levels in the OSAS patients. The increased serum levels of phosphorylated tauobserved in OSAS patients mayresult directlyfrom chronic intermittent hypoxia. Moreover, hypoxia can also promote A?-induced tau phosphorylation by calpain.OSAS has been shownto occur more frequently in AD subjects than in cognitively normal older subjects, and its severity correlates with cognitive impairment. Furthermore,OSAS is associated with an increased risk of dementia. These findings imply that OSAS may promote the development of AD. AD occurs more frequently after the age of sixty, while our OSAS patients were relatively young. Giving that AD type pathology begins 15-20 years before the onset of dementia in sporadic AD, the elevated A? and P-tau levels observed in our patients suggest that OSAS may contribute to the initiation of AD pathogenesis in young patients.Notably, this study was observational, and we were therefore unable to determine the causal relationship between hypoxia and A?. Recent studies have shown that the treatment of severe OSAS with continuous positive airway pressure (CPAP) can slow cognitive decline in patients with AD, which may be due to the correction of intermittent hypoxia. However,whether this benefit is associated with decreased A? and P-tau levels due to CPAP remains to be investigated.This study revealed that increased A? levels in the serum are correlated with the severity of chronic intermittent hypoxia in patients with OSAS, and the results thus support the link between the detrimental effects of hypoxia and neurodegeneration, suggesting that OSAS may contribute to the pathogenesis of AD. Because OSAS is a prevalent disease that affects a substantial proportion of the elderly, the treatment of OSAS may have potential to prevent the occurrence and progression of AD.Study 4: The association between chronic obstructive pulmonary disease and blood AD biomarkersDysfunction of inflammatory pathway is involved in the pathogenesis of AD. Serum IL-6 is increased in patients with AD and could enhance the expression of APPP. CRP, a nonspecific marker of inflammation, is also associated with increased risk of AD. As known,respiratory infection and inflammation are marked characteristics of COPD. COPD patients had elevated levels of CRP and IL-6 in serum and CRP was suggested to predict bacterial infection. Recently, an animal study revealed that infection with respiratory pathogen Bordetella pertussis led to increased glial activation and A? deposition in brain, indicating that respiratory infection and inflammation contribute to AD pathology. Our previous study also showed that common infections and inflammation were associated withincreased serum A? levels. Serum PCT has been used as a biomarker for bacterial infection in patients with COPD. Higher serum A? levels were observed in COPD patients with serum PCT upper the limit of normalin this study. Therefore, infection or/and inflammation might increase A?levels in COPD patients.Numerous studies indicate that hypoxia contribute to the development of AD pathology.Recently, a nationwide cohort study suggests that asthma, another hypoxic pulmonary disease,is associated with increased risk of developing dementia. Sustained or intermittent hypoxia was shown to increase the generation of A? via hypoxia-inducible factor la-mediated upregulation of beta-secretase-1 in vitro. Another in vivo study also confirms that chronic intermittent hypoxia could facilitate A? generation in triple transgenic AD mice. Given this,chronic hypoxia may increase the A? levels in COPD patients as observed in this study. Better pulmonary function in midlife has been proven to be associated with a lower later-life risk of developing AD, indicating that pulmonary function may involve in the pathogenesis of AD.As the pulmonary function is closely related to oxygen content in COPD patients, the higher serum A? levels in severe or very severe COPD patients probably due to their severer hypoxia than mild-to-moderate patients. Recently, prospective studies confirm that COPD increases the risk of MCI and dementia. However, the molecular mechanism for the association of COPD andits risk of dementiais still unclear. AD is the most common type of dementia.Giving the fact thatthe abnormalities of A? are the earliest detectable signs in groups with high risk of dementia and AD, the elevated A? levels in our patients suggest that COPD may contribute to the initiation of AD pathogenesis.In this study, cognitively normal COPD patients had significantly higher serum A? levels than normal controls, implying that cognitively normal subjects with COPD may undergo AD-related pathological changes. Our results supported the hypothesis that COPD patients had increased risk of dementia and AD. If cognitively normal COPD patientswith higher serum A? levels are proven to be preclinical AD, early detection and intervention of those will help to prevent the occurrence and progression of AD.ConclusionCAA and small AP plaques were observed in Wt mice after parabiosis with AD mice for 12 months, and neurodegeneration, neuroinflammation and microhemorrhage were also obvious in paWt mice, indicating that peripheral A? itself can enter the brain and cause AD type pathologies and shedding new insight into the understanding of AD pathogenesis. In the cross-sectional studies, we found blood A? were increased in patients with higher infectious burden,COPD and OSAS,suggesting that systemic diseases affect A? metabolism and AD might be a systemic disease. |
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