Promising New Drug Improves Memory in Mice with Alzheimer’s Disease

Isabelle Wilson, Biological Sciences, Spring 2021

Figure: Diagram of Chaperone-mediated autophagy (CMA) function. This proposed Alzheimer’s drug would increase the number of LAMP2A receptors to increase CMA activity and increase degradation of toxic tau aggregates (Source: Wikimedia Commons).

Alzheimer’s disease is the most common form of dementia, affecting over 5.2 million Americans over the age of 65 (Alzheimer’s Disease, n.d). Pathologically, Alzheimer’s is defined by tau protein aggregates forming tangles inside neurons and beta-amyloid clusters forming plaques between neurons.

Researchers at the Albert Einstein College of Medicine have recently developed a new experimental drug that treats Alzheimer’s disease by increasing the degradation of toxic tau aggregates. This drug, called CA, specifically increases activity of chaperone-mediated autophagy (CMA). CMA contributes to the degradation of intracellular proteins in lysosomes by targeting specific proteins from the cytosol and transferring them to the LAMP2A receptors on the lysosomal membrane (Albert Einstein College of Medicine, 2021). CMA is highly selective as it distinguishes proteins by a recognition motif in their amino acid sequences; this selectivity increases the efficiency of toxic or damaged protein degradation (Cuervo et al., 2014).

Recently, Dr. Cuervo’s research group demonstrated in mice genetically engineered to lack CMA in the brain that loss of CMA activity contributes to the onset and progression of Alzheimer’s disease. Specifically, an abundance of brain cells without CMA was associated with Alzheimer’s symptoms such as impaired walking, memory loss, and proteostasis (ability of the cell to regulate resident proteins) in mice. Furthermore, in the context of human models of Alzheimer’s, Dr. Cuervo’s research showed that CMA activity was partially inhibited in early stages and significantly inhibited in advanced cases (Albert Einstein College of Medicine, 2021).

Additionally, age and neurodegeneration associated LAMP2A receptor deterioration decreases CMA activity as fewer proteins can be loaded onto lysosomal membranes. Dr. Cuervo’s proposed drug, CA, combats this trend by increasing the number of LAMP2A receptors so that chaperones can transfer toxic proteins to increase the activity and efficiency of CMA (Albert Einstein College of Medicine, 2021).

When administered into mouse models of Alzheimer’s disease, CA improved memory, depression, and anxiety. Molecularly, CA reduced tau protein clumps and minimized the effects of gliosis, which is the inflammation and scarring of cells surrounding brain neurons. A lack of demonstrated harmful side effects on surrounding organs validates the drug as a safe and effective new treatment for Alzheimer’s disease (Albert Einstein College of Medicine, 2021).

Ultimately, Alzheimer’s disease is the most dementing disorder in older adults (Alzheimer’s Disease, n.d). Current treatments only mitigate symptoms, and no drugs have been developed to successfully treat the causes of the disease (Albert Einstein College of Medicine, 2021). Dr. Cuervo’s promising drug, CA, would enable the selective activation of CMA thus increasing the degradation of toxic tau aggregates to restore memory and reduce scarring in patients with early or late stages of Alzheimer’s disease (Albert Einstein College of Medicine, 2021).

References

Albert Einstein College of Medicine. (2021, April 22). Experimental drug shows potential against Alzheimer’s disease: Removing ‘garbage’ from brain cells improves memory in mice. ScienceDaily. Retrieved May 4, 2021 from www.sciencedaily.com/releases/2021/04/210422150402.htm

Cuervo, A., Wong, E. Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24, 92–104 (2014). https://doi.org/10.1038/cr.2013.153
Alzheimer’s Disease. Johns Hopkins Medicine. (n.d.). https://www.hopkinsmedicine.org/health/conditions-and-diseases/alzheimers-disease.