| Alzheimer’s disease is a degenerative disease of the central nervous system, whichclinical manifestations is characterized as decreasing of learning ability, loss of memory andcognitive dysfunction. With the development of aging society, AD has become the fourthlargest life killer followed cardiovascular disease, cancer and stroke, it had to be a heavyburden for families and society. Current study showed that there are nearly ten millionpatients with AD in our country, which has the world’s largest AD patients.The main pathological features of AD, including senile plaques formed by β-amyloiddeposition in outside of nerve cells, neurofibrillary tangles formed by tauhyperphosphorylation within the nerve cells and loss of neuronal cells, etc. The pathogenesisof AD is complex, there are several theories for its pathogenesis and β-amyloid cascadehypothesis is being widely accepted. The hypothesis considers that the imbalance of Aβproduction and elimination is the main cause of accumulation of Aβ. There are two mainforms of Aβ protein-Aβ40and Aβ42, Aβ42is the main component of amyloid plaques in thebrain of AD patients. Aβ42is easier to form oligomers, which can cause mitochondrialdamage, oxidative stress, damage synaptic function and induce inflammation, eventuallyleading to neuronal apoptosis.Aβ is producted by β-amyloid precursor protein(APP) via β-secretase and γ-secretasecleavage. Therefore, inhibiting the activity or expression of β-secretase and γ-secretase couldreduce Aβ production. Among them, β-site Amyloid precursor protein Cleaveing Enzyme1(BACE1) is a key enzyme of Aβ generation process. Numerous studies indicate thatinhibition of BACE1gene or knockout it, can significantly reduce the expression ofβ-secretase enzyme in AD mice brains, and then reduce Aβ generation, significantly improvedthe AD model mice learning and memory Indicated that BACE1can be as a treatment targetfor AD. In addition, the cell membrane protein-APP is also a direct influence on the amount ofAβ generation, so APP is also an important target for AD.There are exist degrading system of Aβ in the body, which can clear Aβ, reduce Aβdeposition in the brain. Aβ degrading enzymes including insulin-degrading enzyme（IDE）andneprilysin（NEP）. Studies have reported that transgenic technology to IDE or NEP gene intoAD mouse model, can significantly increase the clearance of Aβ, reducing Aβ deposition inthe brain. Therefore, improving Aβ degrading enzyme expression or activity, promoting the degradation of Aβ is also an important aspect to treat AD. Aβ can spontaneously aggregate toform oligomers in the brains, which have a variety of forms and the form of soluble oligomerscan cause larger neurotoxicity. Therefore, drugs which can inhibit or reduce the toxicity of Aβoligomerization state and protect the nerve cells in the brain, is also an important strategy forthe treatment of AD.In summary, through drugs intervene the generation or removal process of Aβ, andregulate metabolic balance to reduce or inhibit Aβ accumulation is an important strategy forthe treatment of AD. Currently, the drugs treatment of AD patients mainly includes NMDAreceptor antagonists and cholinesterase inhibitors, and drugs about Aβ metabolism are stillblank. Therefore, it has an important significance that discussing the effect of naturalmedicine on Aβ accumulation to treatment of AD.Berberine (BBR), also known as berberine hydrochloride, is extracted from traditionalChinese herb-Coptis chinensis, which belongs to isoquinoline alkaloid family, shows potentpharmacological effects, including anti-inflammatory, antibacterial, anti-oxidative stress,inhibition of cholinesterase activity, and neuroprotective effects of brain tissue sufferedischemia-reperfusion injury. The neuroprotective effection of berberine indicates that has thepotential to treat AD. Early studies described that berberine can reduce the accumulation ofAβ protein, improve symptoms of dementia in AD model mice. But the respects of berberineon Aβ degrading enzyme and the neuroprotective effect of Aβ oligomerization state have notbeen reported in the metabolic pathway of Aβ.In this study, we study the influence of berberine on Aβ metabolism and the protection ofAβ cytotoxicity：1. The effects of berberine on the degradation and generation of Aβ in vitro. The resultsshowed that berberine can reduce the generation of Aβ in a dose-dependent manner.10μMberberine can down-regulate the Aβ40and Aβ42with reduction of33.60±7.65%and39.40±0.93%. Further studies have shown that berberine through activating PPARγ-IDE signalingpathway reduces the accumulation of Aβ. The study also found that berberine did not affectthe expression of APP and BACE1, which are important in the process of Aβ production.2. To study the protective effect of berberine on neurotoxicity induced by Aβ aggregatein N2a cells, the researchers found that berberine can play a protective role in adose-dependent manner, The survival rate of N2a cells in10μM berberine group was superthan Aβ group, and the gap between the two groups was37.11±4.08%. Further studies showed that the neuroprotective effect of berberine on survival rate of N2a cells was relatedwith IDE, the result showed that adding IDE inhibitors the survival rate of N2a cells candecrease by15.20±3.71%. The mechanism may be that berberine can activate PPARγ-IDEsignaling pathway to promote the degradation of extracellular Aβ aggregate and inhibit thecytotoxicity of Aβ aggregate. |
