The Immunologic Mechanism In The Progression Of Alzheimer’s Disease Model And Exercise Intervention

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder characterized by progressive loss of memory and other cognitive function. There are two kinds of AD, one is early-onset familial AD, the other is late-onset AD. The vast majority of AD cases are the late-onset sporadic form of the disease. The disease symptoms usually start after 60 years old. So late-onset AD are bound up with aging.In the AD, hyperphosphorylation of tau aggregates inside the neuronal cell body is the first pathological feature; the second pathological feature of AD is the formation of neuritic amyloid plaques, and neuroinflammations is considered the third pathology feature.The mechanism of glial involvement in the pathogenesis of AD was that the insoluble fibrillar Aβ gathered, and actived glial triggering a series of inflammatory responses. The activation of MG produce the complement composition, prompting reactive oxygen species which cause neurons denaturation, and produce various proinflammation cytokine and chemokine, inducing inflammation respone with free radical, causing the neurotoxicity. The proinflammatory cytokine activate AS and participation in the brain local inflammatory process.But some studies have found that the Aβ did not form senile plaques necessarily, in the normal brain of old also exist the diffuse gathered Aβ. So the gathered A P is the produce of aging, and is not the directly cause of AD. In the study of MG role in AD, it have found that the morphology of MG is concerned with aging. The morphology of MG changed and became dystrophy following aging, and the functions of MG also changed. An other finding show that the neurodegenerative changes in AD are not accompanied by microglial (MG) activation but instead by microglial dystrophy which likely reflect the degeneration of these cells. The tau-protein phosphorylation and Aβ plaques sites were around with MG, its morphology is not activated but dystrophy. The degradation and the loss in protection function of MG is one of the main causes of AD.The role of AS in AD also has a different viewpoint. In chronic neurodegenerative diseases, more and more research shows that actived AS as inherent immunity cells, participate in the immune identification, immune adjustment, and the inflammatory process. The funtions of AS changed from metabolic support cells to immune cells. But astrocytes atrophy was found in transgenic AD animal. It had been found that consistent reduction in the GFAP expression which progressed with age. There was a slight reduction in astrocyte complexity that was directly associated with a decrease in the number of processes and overall decrease in both surface and volume of astrocytes.There are two quite different hypothesis about the role of MG and As in coming on AD. One is that the excessive activation of MG and AS causing the inflammation respones is one of the reason of AD. The performances are the increased of proinflammation cytokine and the excessive activation of MG and AS. The other is that the aging of MG and AS, the loss of function for protection are the the reason of AD. The performance is the dystrophy of MG and AS.According to the above two hypothesis, the SAMP8 which did not form amyloid plaque was used for the experiment materials to study the morphology changes and functions of MG and AS, by the WMW test, immunohistochemistry, PT-PCR, western blot, luminex methods. And the immunologic mechanism of exercise intervention were studied.The results indicated that the cognizance of the mice aged 2 and 5month was insignificant differences, the morphologies of microglial and astrocytes were hypertrophy, more branch, and were activated. But the cognizance of the mice aged 8month was significant decrease, the decrease in female mica was more serious. The morphologies of microglial and astrocytes in female brain had significant changed. The hippocampus tissues surrounding MG began to appear empty bubble, the body of MG start to atrophy, branch fracture, and the body of AS were fuzzy, incomplete, reduced branch.The AS number of complete cell significant decrease and the decrease in the hippocampus of female mica was more serious. The expression of CDllb and GFAP also significant decrease. The study results support the MG and AS aging theory.The function changes of MG and AS following aging were studied from three aspects, including the chang of expression of BDNF and GDNF, the protein level of GDNF; the change of expression of TLR2, TLR4 the markers on MG and AS surface, the expression of MyD88 in the signal pathway; the change of the level of proinflammatory cytokines IL-1β, TNF-, IFN-γ and chemokine MCP-1. Following aging, the expressions of BDNF and GDNF were significant decreased, the same result of the protein level of GDNF was obtain. The phagocytosis of MG reduced. The levels of proinflammatory cytokines and chemokine increased significantly. According to the increase of proinflammatory factor, one reason is the MG and AS aging, repair function damage causeing sustained release of proinflammatory cytokines; another reason is the permeability of BBB increased in SAMP8 mice, the increased chemokine MCP-1 recruited the phagocyte from periphery into CNS, promoted inflammation respond.MG and AS are immune cells in the central nervous system, the functions of activated immune cells are immune repair, if immune repair function can’t finish, it will be possible to promote accumulation of proinflammation cytokine. Acorrding to the theoretical model for the healthy response to stress-induced mild brain injury, the healthy repair process include two phases:An initial neuroinflammatory phase of brain injury repair inhibits growth while clearing the lesion of cellular debris. During this initial phase, released proinflammatory cytokines induce a motivational reprioritization, sickness behavior that promotes convalescence. As the repair process transitions to the regenerative phase, trophic influences and neurogenesis gain dominance and inhibit proinflammatory processes. Sicknesss ymptoms ultimately resolve and a final refinement phase of the repair response is carried out.Oxidative stress was appeared at 3 month age, hyperphosphorylation of tau was appeared at 5month age in SAMP8 mice. Oxidative stress and hyperphosphorylation of tau would induced mild brain injury, the injury could active MG and AS. The functions of MG and AS are in normal level, they are able to complete the process of repair. Following MG and AS aging, the repair process was stopped in the initial neuroinflammatory phase, inducing the the accumulation of proinflammatory cytokine. So the increased chemokine MCP-1 recruited the phagocyte from periphery into CNS, promoted inflammation respond.Up to now, there is on effective drug to cure AD, while exercise offers the only intervention measures which cure AD without durg. The results indecated the regular physical exercise of all experiment process or early stage before exhibiting AD symptoms could increase cognition ignificantly. The physical exercise after exhibiting AD symptoms could delay and improve cognition. The cognition of 8 month aged female mice is equal to that of male mice.The mechanism of exercise was that exercise delay the aging of MG and AS, delay the decrease of AS, esure the functions of MG and AS. Exercise has been found to be a successful preventative measure in increasing the number of AS, increasing the expression of BDNF and the level of GDNF, and increasing the expression of TLR2and Myd88, and the phagocytosis of MG, and decreasing the level of proinflammatory cytokines. Exercise has been found to delay aging and encure the funcition of Glial cells.