Alzheimer'sdisease (AD) is a serious neurodegenerative disease. Patients usually havesymptoms of memory and learning ability decline, accompanied by emotionalregulation disorder and loss of motor ability, which greatly affects thedevelopment of individuals, families and even society. At present, about 50million people worldwide suffer from Alzheimer's disease. This figure isexpected to increase to 152 million by 2050. At present, the global annual costof treating and caring for AD patients has reached $1 trillion, and this figurewill double by 2030.
Since1998, more than 100 drugs trying to treat this disease have entered clinicaltrials, but only 7 drugs have been approved. What is more regrettable is thatin recent years, the drugs developed by major pharmaceutical companies in theworld have suffered varying degrees of failure. The drug Aduhelm, which Biogenhas just approved, has also been questioned, which has cast a shadow on humanbeings to conquer AD.
Recently,Professor Ana Maria Cuervo found that activation of chaperone mediatedautophagy (CMA) can reverse the key symptoms of Alzheimer's disease in mice.The related results are entitled "chaperone mediated autophagy preventscollapse of the neuronal metastable proteome" and was published online in Cell on April 22, 2021. Professor Ana Maria Cuervo suggests that drugs thatactivate CMA may bring hope for the treatment of neurodegenerative diseasessuch as AD. However, so far, there is no drug to activate CMA in clinic.
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CMAis a selective autophagy that can gently degrade various soluble proteins. Theactivity of CMA decreased with age, which increases the risk of harmful proteinaggregation. In fact, the common feature of AD and other neurodegenerativediseases is the presence of a large number of toxic protein aggregates in thepatient's brain.
OnJuly 21, 2021, Xia Hongguang group of School of basic medicine sciences ofZhejiang University/Liangzhu Laboratory published a research paper entitled"metformin activated chaperone mediated autophagy and improved diseasepathologies in an Alzheimer disease mouse model" online in Protein& Cell. Metformin was identified as a new CMA inducer byhigh-throughput drug screening. it was revealed for the first time that theactivation of CMA by Metformin depends on TAK1-IKKα/β-Hsc70 signal pathway. Atthe same time, the study also found that APP, the precursor of Aβ is a new CMAsubstrate; They further proved that feeding APP/PS1 mice with metformin oroverexpression of Hsc70 in the hippocampus of APP/PS1 mice can activate CMA andsignificantly delay the progression of AD disease. This study provides an ideathat metformin can be used in clinical treatment of AD, and reveals a new mechanismof metformin in the treatment of AD by inducing CMA.
FigureMetformin induces CMA activity and promotes the degradation of APP
