The Evidence And Preliminary Mechanism Of Aβ-induced Hyperphosphorylation Of Protein Tau

Background: Alzheimer’s disease(AD), also called senile dementia, is a progressiveneurodegenerative disease with clinical cognitive and memory loss. Its clinicalmanifestations are deteriorating cognitive and memory function, progressiveneurodegenerative activities of daily living, along with a variety of neuropsychiatricsymptoms as well as behavioral disorders. Currently, a hundred of theories of ADpathogenesis, including "amyloid β-peptide (Aβ) hypothesis" and "tau hypothesis" whichare the most accepted mainstream doctrines. Among these, the Aβ hypothesis is indicatedthat owing to developmental and metabolic disorder, Aβ cannot be promptly removed andturns into deposition of brain in senile plaques, which eventually leads to the death ofneurons, inhibition of neuronal regeneration, thus the occurrence of AD. The tau hypothesisis considered hyperphosphorylation of protein tau losses ability of maintaining andaccelerating structural of a steady neuronal microtubules, changes its cytoskeleton, whichresulting in the appearance of neurofibrillary tangles, neuron death, and then a series of ADpathological features.Recent studies have been identified that Aβ of the soluble oligomeric state hasstronger neurotoxicity. Research also have pointed out that the Aβ induceshyperphosphorylation of protein tau, whose path is activating certain kinases to stimulatephosphorylation of protein tau. Meanwhile, there is growing number of evidencedemonstrate that the joint pathogenic hypothesis of “Aβ hypothesis" and "tau hypothesis" ismore reasonable.In order to investigate Aβ induced hyperphosphorylation of protein tau, then togethercausing in occurrence of AD, this essay will draw the following conclusions:(1) Aβ is thesource of AD pathogenesis. It produces and eliminates imbalance, which bring about the emergence of the following characteristics of AD pathology;(2) The soluble oligomericform of Aβ which is the main pathogeny of AD due to its stronger neural toxicity.(3) Aβinduces hyperphosphorylation of protein tau, and causing it to dissociate from nervemicrotubule, finally the growing number of protein tau and finally neural loss. Both Aβ andprotein tau will lead to the development of AD.(4) Aβ activates kinase cdk5that promotesphosphorylation of protein tau.Methods:1. Using Aβ-intrahippocampal injection method to prepare animal mice models whichdivided into BALB/c-experimental group and the control group. Experimental groupswere injected with Aβ1-42oligomers (4μg/2μl) into the CA1area of hippocampusbilaterally; control groups were injected with equal volume of normal saline (NS).Animals were sacrificed at7d after model injection.2. Comparing the results between Aβ1-42group and NS group by Hematoxylin-eosinstaining.3. Detecting the deposition of Aβ1-42in experimental group by immunohistochemistrystaining, and compare the difference between amount of deposition and location in eachtime.4. Using immunohistochemistry and Western blot to detect the expression of cdk5in eachgroup.5. Using immunohistochemistry and Western blot to detect the expression of protein tau.6. applying RT-PCR to detect the expression of protein tau.Results:1. Both NS group and Aβ1-42group have apparent inflammatory injured region. Compareto NS group, the area in Aβ1-42group mice was much more particularly obvious, eveninduced the degeneration of neurons.2. Immunohistochemistry showed that Aβ were mainly deposited in area of hippocampusin the experimental groups. Within7to21days after operation, the area of Aβ weredecreased gradually. 3. Immunohistochemistry and western blotting showed that there was positive expressionwithin the subgranular zone (SGZ) of dentate gyrus and injection of hippocampus.Compare to NS group, the expression of cdk5increased dramatically in Aβ group withsignificant difference(P<0.01).4. Immunohistochemistry and western blotting showed that there was positive expressionwithin the subgranular zone (SGZ) of injection of hippocampus and dentate gyrus.Compare to NS group, the expression of protein tau increased dramatically in Aβ groupwith highly significant difference(P<0.01).5. RT-PCR showed that the expression of protein tau in Aβ group was much dramaticallyhigher than in NS group.Conclusions:1. The soluble oligomeric form of Aβ induces hyperphosphorylation of protein tau.2. Aβ activates kinase cdk5that promotes phosphorylation of protein tau.3. This study shows that Aβ42may be the starting factors in the pathological process toAD...