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Experimental Drug shows promise for treating Alzheimer’s Disease

Scientists have engineered a possible therapeutic drug that mitigated the symptoms of Alzheimer’s Disease in mice models. 

The proteins made in the body undergo degradation via autophagy and their component amino acids are recycled so as to maintain proteostasis. The degradation happens either in the proteasome or in the lysosome, which are the ‘garbage disposing organelles of the cell. The degraded proteins enter into the lysosome via a vesicle or with the help of transport chaperone proteins in a process called Chaperone Mediated Autophagy (CMA). These autophagic processes, especially CMA, decrease in efficiency as we age. By the time a person reaches 70-80 years of age, their CMA activity reduces by 30%. Soluble proteins become insoluble due to lack of proteostasis and can accumulate in different parts of the body leading to degenerative disorders.

Alzheimer’s Disease, one such neurodegenerative disorder associated with improper proteostasis, is characterised by dementia, short-term memory loss, disorientation, linguistic issues, several mood and behavioural changes. In patients with this disorder, defective tau proteins, among other toxic proteins, accumulate to form amyloid plaques and neurofibrillary tangles in the brain hindering neuronal function. Under normal circumstances, the faulty tau proteins are carried by the chaperones through a LAMP2A (lysosome-associated membrane protein) receptor into the lysosome where it is broken down. 

In a study published in Nature Communications, Benjamin Cabellero and his colleagues at Albert Einstein College of Medicine observed that the acetylated form of these tau proteins inhibited the CMA pathway. This phenomenon altered tau homeostasis and aggravated neurodegeneration in mice models. In another study, published in Cell, Prof. Ana Cuervo and her team also from Albert Einstein College of Medicine wanted to further unravel the relationship between CMA and Alzheimer’s. They used genetically modified mice that had neurons lacking CMA. The absence of CMA in one brain cell was capable of causing short-term memory loss and impaired walking in the mice. 

The researchers suspected if the converse was true i.e if people who had Alzheimer showed impaired CMA activity. They took mice suffering from Alzheimer’s and observed their CMA activity levels. Amyloid plaques and neurofibrillary tangles were visible in the brains of these mice. The CMA activity in their brains was also significantly reduced as compared to the control mice models. Through single-cell RNA-sequencing, they also observed the decreasing CMA activity in mice with early onset of Alzheimer’s disease. 

Based on these findings, Prof. Cuervo and her team engineered a possible therapeutic drug that could help reinstate the CMA system in order to ‘clean’ out the damaged tau and other proteins. The same number of LAMP2A receptors are produced throughout life, but upon aging, these receptors deteriorate. The drug called CA works by increasing the number of LAMP2A receptors to youthful levels so that the chaperones can efficiently carry the damaged proteins into the lysosomes which can then be digested. 

The researchers administered CA in two different mouse models of Alzheimer’s disease for over 4-6 months. Both the disease mouse models showed improved memory, reduced depression, and anxiety levels similar to that of the healthy control mice. The number of tau protein clumps in the brain were comparatively lesser than that of the untreated animals. Walking ability improved in the animal models in which it was a problem. The CA drug also reduced gliosis, which is the inflammation and scarring of tissues surrounding the brain neurons. Gliosis is one of the contributing factors in several neurological disorders. The treatment with the CA drug did not cause much damage to any of the other internal organs. 

Since animal models were used for the study, it correlates with human functioning. This drug reversed the key symptoms of Alzheimer’s in mice. A substantial amount of research will be required to further test the effectiveness of the drug in humans. “We were encouraged to find in our study that the drop-off in cellular cleaning that contributes to Alzheimer’s in mice also occurs in people with the disease, suggesting that our drug may also work in humans,” asserts Dr Cuervo. 

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