Intestinal Endotoxemia Role In The Pathogenesis Of Alzheimer's Disease And Related Mechanisms

Alzheimer's disease is the most prevalent form of dementia affecting more than 20 million people worldwide.AD was originally recognised by AloisAlzheimer in 1907 as a separate form of dementia.Furthermore,as a consequence of the worlds aging population,the prevalence of AD is expected to increase.This highlights the importance of research investigating the mechanisms behind the development of the disease.Apart from the recognisable behavioural differences,it is difficult to positively diagnose someone with Alzheimer's during the early stages of the disease.However the AD brain shows a consistent pathology amongst patients, with amyloid aggregates and neurofibrillary tangles evident in the AD brain.Intense research has identified genes involved in the development of these pathologies,namely the amyloid precursor protein and the presenilins.The increasing knowledge on AD pathogenesis has revealed the complex nature of this disease and highlights the need to elucidate the molecular mechanisms involved.This review discusses the current knowledge of the molecular mechanisms of Alzheimer Disease,focusing on amyloidogenesis,the role of the presenilin genes and the importance of animal models to further elucidate the mechanisms behind the development of the disease.The most common form of AD in the population(approximately 90%) occurs sporadically and is late in onset,usually occurring after 65 years of age.Familial Alzheimer's disease(FAD),only accounts for approximately 10%of cases and symptoms usually occur before the age of 65.The mode of inheritance of AD differs for each type.The majority of FAD and sporadic AD cases have a complex inheritance,while only 10%of FAD cases are inherited in an autosomal dominant pattern.In affected individuals the disease causes a progressive and permanent decline in memory and cognitive abilities.The first cognitive area affected is episodic memory.During disease progression,attention,executive functions,semantic memory,language and spatial orientation all begin to deteriorate.However the molecular,cellular and pathological triggers for the onset of the cognitive deterioration are poorly understood.Since this original observation the two main histological features of amyloid plaques and neurofibrillary tangles(NFT) have been described in the AD brain.These features are found to be present in the temporal neocortex and hippocampal regions of the AD brain.The hippocampus resides in the cerebral cortex of the forebrain and is thought to be involved in memory storage.Amyloid plaques and NFTs result from an aberration in deposition of the amyloid beta peptide(Aβpeptide) and the hyperphosphorylated tau protein respectively and these depositions lead to neuronal loss and neurotoxicity in the AD affected brain.Accumulation of Aβpeptides may be the key event in pathogenesis of AD.The exact mechanism by which Aβpeptide deposition induces neurotoxicity is unclear,but it appears the oxidative stress plays an important role.Oxidative stress is extensive in AD and Aβpeptides stimulate oxidative stress by both direct and indirect mechanisms.Aβpeptides by themselves may act as enzymes,as they are capable of directly producing hydrogen peroxide and generating free radicals through metal ion reduction.As well,Aβpeptide can bind to mitochondrial proteins resulting in the generation of free radicals.Furthermore,Aβpeptides generate oxidative stress via neuroinflammation. Considerable evidence has supported that neuroinflammation is associated with AD pathology. The death of neurons observed in AD is partly attributed to the activation of two major brain cell types,astrocytes and microglia that participate in the immune/inflammatory response to Aβdeposition.However,these cells can have both neuroprotective and neurodegenerative functions.Intestinal endotoxemia(IETM) was establish by Dewu Han in 1995,it claims that liver injury induced by various pathogenic factors(such as hepatitis virus,ethanol,drugs and hepatotoxicants,etc.) through their respective special pathogenesis is referred to as "primary liver injury"(PLI).Liver injury resulted from endotoxin(lipopolysaccharide,LPS) and the activation of Kupffer cells by LPS while intestinal endotoxemia(IETM) occurred during the occurrence and development of hepatitis is named the "secondary liver injury"(SLI).The after which has lost their own specificities of primary pathogenic factors is ascribed to IETM.The "secondary liver injury" is of important action and impact on development and prognosis of hepatitis.More severe IETM commonly results in excessive inflammatory responses,with serious hepatic necrosis,further severe hepatitis and even induces acute liver failure.Recent research show that IETM can be found in shock,stress,pancreatitis,and so on.In IETM,LPS plays a important role,it can lead inflammatory reaction.All inflammatory reactions are also immune reactions.It is the innate immune system that is first called into action. Later,the adaptive system may also respond.Chronic inflammation signifies that an immune reaction is being sustained.That is because healing has failed to take place.Chronic inflammation may involve the innate immune system,the adaptive immune system,or a combination of the two.AD is the prototypical autotoxic disorder.Classical immunologists had originally declared that it was a sterile,noninflammatory degenerative condition.The conclusion was based on the absence of infiltrating lymphocytes and monocytes which were easily observed in CNS infections and in presumed autoimmune diseases such as multiple sclerosis.This observation vindicated Hortega's original conclusion in 1919 that microglia were phagocytic cells of mesodermal origin.Moreover,it established that chronic infammafion could exist in the absence of leukocyte infiltration.Two subsequent steps showed that the inflammation was self-damaging.The first was immunohistochemical,in which dystrophic neurites being damaged by the membrane attack complex of complement could be observed in AD tissue.The second was epidemiological,in which those taking anti-inflammatory agents appeared to be spared from AD.If the inflammation observed immunohistochemically had been beneficial instead of harmful,taking anti-inflammatories should have increased the risk of AD,and if they were merely cleaning up debris,then they should have had no effect.These epidemiological findings,which have been replicated in more than 20 studies,clearly show that the inflammation is contributing to the disease pathology,and that long-term consumption of NSAIDs reduces the risk of AD from twoto five fold.Any reservations that might still be held that microglia are the sentinels of the brain that respond to disease pathology should have been dispelled by the recent in vivo movies.When an abnormality was induced by laser damage to a capillary,the microglia immediately changed to an activated morphology.Within minutes,they began migrating to the lesion site where they sealed off the affected area and commenced phagocytosing the extravasated blood.Microglias are the brain representatives of van Furth's monocyte phagocytic system.Their counterparts,such as Langerhan's cells of the skin,Kupfer cells of the liver,osteoclasts of bone, and macrophages in many organs,are tissue-based phagocytes which can be presumed to carry out similar functions to microglia throughout the body.While it is only speculation at this stage, it might be anticipated that all cells of the monocyte phagocytic system would respond to pathological challenges in a similar fashion to those observed of brain microglia.Inflammatory cytokines are more powerful mediators and are therefore a better target. Enbrel and Remicade,which block TNF,have had great success in treating rheumatoid arthritis. They are globulins which do not cross the blood-brain barrier and are therefore not suitable for CNS diseases.Nevertheless,they illustrate the promise of small molecules which could reach the brain and block the actions of TNF.Presumably,blockers of IL-1 and IL-6 would also be effective.Blockers of complement activation,especially the membrane attack complex,are also attractive targets for future therapy.As well,blockers of intracellular pathways that promote DNA transcription of inflammatory mediators should be effective.There are numerous reviews that cover the toxic effects of inflammatory mediators and the spectrum of possible agents or pathways to block in order to reduce such effects.In order to explore the releationship between IETM and AD,we carry out this research. Our research includes three parts:1,Research of the AD rat model by intraperitoneal injection with D-Gal and AlCl₃.Methods:We established AD rat model by subjected to 90 days of intraperitoneal injection with D-galactose(60mg·kg^-1·d^-1) and aluminum trichloride(25mg·kg^-1·d^-1) to establish the Alzheimer disease's model,the TP,POD,T-AOC,CHAT,ACHE,NOS,NO in rat brain were detectd by kits.The learning and memory ability of the rats were observed by Morris water maze. The level of apoptosis,Tau,Aβ1-40 and express of APP,PS1 and BACE of rat brain were explored by TUNEL,ELISA,Immunohistochemistry and RT-PCR.Results:The ability of learning and memory is obviously decreased in the rats treated with D-Galactose and AlCl₃ compared with the normal rats,while the express of APP,PS1 and BACE mRNA is increased.And there is apoptosis,deposition of Aβ1-40 and Tau in AD rat model.Conclusion:Intraperitoneal injection with D-Gal and AlCl₃ can make AD rat model.2,Research about the role of IETM in AD.Methods:We explored the level of LPS,TNF-α,IL-1β,IL-10,DAO,Gln and Glutaminase in plasma of rat,the functional status of KC by immunohistochemistry,the level of S-100βin plasma and ZO-1 in brain by ELISA and Western blot.Results:The level of LPS,TNF-α,IL-1β,IL-10,DAO,Gln and S-100βin AD rat model is raise up besides Glutaminase and ZO-1.Conclusion:The intestinal mucosa barrier and BBB were damaged,phagocytosis of KC was decreased.The level of IETM in AD model was step up.3,The mechanism of IETM influenced AD by use LPS to induce BV-2.Methods:BV-2 was cultured in DMEM with FCS,PCN and STM.Set group as:BV-2+Aβ: 30min,1h,3h,6h,12h,24h;BV-2+LPS:30min,1h,3h,6h,12h,24h.Observe the morphous in inverted microscope.Detect the phagocytosis of BV-2 with polystyrene and expression of OX-42 with immunofluorescence.The level of TNF-α,IL-1βin clear supernatant was detectd by ELISA,the expression of p38,JNK,NF-κB was detect by Western blot.Apoptosis was detectd by flow cytometry and[Ca²⁺]I was detect by Confocal Laser Scanning Microscope.Results:LPS and Aβ1-40 can induce BV-2,promote it phagocytosis,up-regulation the expression of OX-42 and secretion of TNF-α,IL-1β,apoptosis and[Ca²⁺]i was increased.The expression of p-p38,p-JNK and NF-κB increased too.Conclusion:LPS can activate BV-2 to release TNF-α,IL-1β.Latter lead to Inflammatory reaction through signal transduction,such as p38,JNK,NF-κB,finally induce AD. Conclusion1,Intraperitoneal injection with D-Gal and AlCl₃ can eatablish AD rat model.2,The level of IETM in AD model was step up.The intestinal mucosa barrier and BBB were damaged,phagocytosis of KC was decreased.3,LPS can activate BV-2 to release TNF-α,IL-1β.Latter lead to Inflammatory reaction through signal transduction,such as p38,JNK,NF-κB;LPS can induce BV-2 apoptosis and calcium overload.Through these channels LPS finally induce AD.In conclusion,there is IETM in AD,which play a important role.