Alzheimer's disease (AD) is a serious neurodegenerative disease. Patients usually have symptoms of memory and learning ability decline, accompanied by emotional regulation disorder and loss of motor ability, which greatly affects the development of individuals, families and even society. At present, about 50 million people worldwide suffer from Alzheimer's disease. This figure is expected to increase to 152 million by 2050. At present, the global annual cost of treating and caring for AD patients has reached $1 trillion, and this figure will double by 2030.
Since 1998, more than 100 drugs trying to treat this disease have entered clinical trials, but only 7 drugs have been approved. What is more regrettable is that in recent years, the drugs developed by major pharmaceutical companies in the world have suffered varying degrees of failure. The drug Aduhelm, which Biogen has just approved, has also been questioned, which has cast a shadow on human beings to conquer AD.
Recently, Professor Ana Maria Cuervo found that activation of chaperone mediated autophagy (CMA) can reverse the key symptoms of Alzheimer's disease in mice. The related results are entitled "chaperone mediated autophagy prevents collapse of the neuronal metastable proteome" and was published online in Cell on April 22, 2021. Professor Ana Maria Cuervo suggests that drugs that activate CMA may bring hope for the treatment of neurodegenerative diseases such as AD. However, so far, there is no drug to activate CMA in clinic.
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CMA is a selective autophagy that can gently degrade various soluble proteins. The activity of CMA decreased with age, which increases the risk of harmful protein aggregation. In fact, the common feature of AD and other neurodegenerative diseases is the presence of a large number of toxic protein aggregates in the patient's brain.
On July 21, 2021, Xia Hongguang group of School of basic medicine sciences of Zhejiang University/Liangzhu Laboratory published a research paper entitled "metformin activated chaperone mediated autophagy and improved disease pathologies in an Alzheimer disease mouse model" online in Protein & Cell. Metformin was identified as a new CMA inducer by high-throughput drug screening. it was revealed for the first time that the activation of CMA by Metformin depends on TAK1-IKKα/β-Hsc70 signal pathway. At the same time, the study also found that APP, the precursor of Aβ is a new CMA substrate; They further proved that feeding APP/PS1 mice with metformin or overexpression of Hsc70 in the hippocampus of APP/PS1 mice can activate CMA and significantly delay the progression of AD disease. This study provides an idea that metformin can be used in clinical treatment of AD, and reveals a new mechanism of metformin in the treatment of AD by inducing CMA.
Figure Metformin induces CMA activity and promotes the degradation of APP
