An Anti-Cancer Drug Could be New Hope for Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disease, occurring primarily in the elderly, and its prevalence is increasing as the average human lifespan increases. Current treatments for AD focus on controlling symptoms and slowing the progression of the disease by targeting the accumulation of beta-amyloid (Aβ) or tau protein plaques in the brain.

AD disrupts the glucose metabolism needed to fuel a healthy brain. Essentially, the metabolic decline robs the brain of energy, which in turn impairs thinking and memory. Recent proteomic studies have also shown that astrocyte and microglia metabolism is significantly disrupted in patients with AD.

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Researchers from Stanford University and other institutions collaborated on a research paper. The study shows that blocking indoleamine 2,3-dioxygenase 1 (IDO1) restores glucose metabolism and rescues memory and brain function in astrocytes of the brain in a mouse model of AD. IDO1 inhibitors are currently being developed for the treatment of different types of cancer, suggesting that this drug, developed for the treatment of cancer, has the potential to be a new treatment for neurodegenerative diseases such as AD.

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An Enzyme Expressed in Astrocytes - IDO1

Lactic acid produced by astrocytes is exported to neurons to fuel mitochondrial respiration and support synaptic activity. Recent studies have shown that IDO1, an enzyme expressed in astrocytes, plays an important role in a number of neurodegenerative diseases, including AD.

IDO1 is the rate-limiting enzyme in the conversion of tryptophan (TRP) to kynurenine (KYN), which acts as a metabolite to cause immunosuppression in inflammatory and tumor environments by interacting with the aromatic hydrocarbon receptor (AhR). IDO1 activity is significantly up-regulated by a wide range of immunogenic stimuli and, in the brain, is expressed in astrocytes and microglia, but not in neurons, and its levels can increase in response to inflammatory stimuli. Overactivation of the KYN pathway in astrocytes results in the inability of astrocytes to produce enough lactate to serve as a source of energy for neurons, thereby disrupting healthy brain metabolism and damaging synapses.

Thus, the team hypothesized that an increase in IDO1 and KYN triggered by the accumulation of Aβ or tau proteins would disrupt healthy brain metabolism and lead to cognitive decline.

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IDO1 Inhibitors Tested in AD Mouse Models

IDO1 is well known in oncology, and drugs that inhibit IDO1 activity and KYN production are already undergoing clinical trials in multiple cancer therapies. Therefore, the team tested IDO1 inhibitors using preclinical models - in vitro cell models with Aβ proteins and tau proteins, in vivo mouse models, and in vitro human cells from patients with AD.

• The brain relies heavily on glucose to drive many processes, so losing the ability to efficiently utilize glucose for metabolism and energy production can lead to metabolic decline, especially cognitive decline. And this study allows us to visualize precisely how the brain's metabolism is affected by neurodegenerative pathologies.
• IDO1 inhibitors improved glucose metabolism in the mouse hippocampus, repaired defects in astrocyte function, and enhanced their cognitive and spatial memory abilities. Blocking KYN production by inhibiting IDO1 restored the ability of astrocytes to produce lactate to nourish neurons and also rescued behavioral abilities.
• Blocking IDO1 is protective against both of these two different pathologies, Aβ protein and tau protein. In addition, IDO1 may also be associated with diseases with other types of pathology, such as Parkinson's disease, as well as a broad spectrum of progressive neurodegenerative diseases known as tauopathies.

Inhibition of the IDO1 enzyme, which blocks its mediated conversion of TRP to KYN, rescued hippocampal memory function in a mouse model of AD by restoring astrocyte metabolism. Aβ proteins and tau proteins activate IDO1 in astrocytes, increasing KYN and inhibiting glycolysis in an aromatic hydrocarbon receptor-dependent manner. Inhibition of IDO1 improves glucose metabolism in the hippocampus and rescues long-term enhancement of the hippocampus in a model of Aβ protein and tau protein pathology. In astrocyte and neuronal co-cultures from KYN patients, inhibition of IDO1 increased the ability of astrocytes to produce lactate and be taken up by neurons.

Targeting PNS in Tumors

Recent research has been exploring the connection between cancer therapies and neurodegenerative diseases such as AD. One such area of interest involves the repurposing of anti-cancer drugs, particularly those targeting growth factors and cancer pathways, to find potential treatments for AD. Here are some key research points regarding this topic.

• Mechanistic Overlap: Some molecular mechanisms and signaling pathways involved in cancer share similarities with those involved in AD. For example, neuroinflammation and oxidative stress are critical in both conditions.
• Potential Candidates: Certain anti-cancer compounds such as those that affect the mTOR pathway have shown promise in both extending lifespan in models of aging and reducing amyloid pathology in models of AD.
• Drug Repurposing: Researchers are investigating existing anti-cancer drugs for their neuroprotective effects. For instance, drugs that inhibit certain cancer pathways may also modify pathways dysregulated in AD, helping to mitigate neurodegeneration.

The search for effective treatments for AD continues to evolve, and the exploration of anti-cancer drugs offers hope for new therapeutic options. Further research, particularly in clinical trials, will be crucial to establish the efficacy and safety of such approaches in Alzheimer's patients.

Reference

1. Minhas, Paras S., et al. "Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies." Science 385.6711 (2024): eabm6131.

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