29 Aug Anavex Investigating Amyloid Beta-Based Therapy for Alzheimer’s Disease

Alzheimer’s disease is the most common condition that leads to a gradual loss of memory and thinking skills. It’s marked by the buildup of plaques and tangles in the brain. It’s one of many different areas where Anavex Life Sciences is focusing its research as part of its mission to develop effective therapeutics for neurodegenerative disorders.

In 1984, researchers discovered that a protein called amyloid beta is a key part of the plaques that aggregate in the brain. This led to the theory that Aβ is central to Alzheimer’s, known as the “amyloid cascade hypothesis.” Since then, most Alzheimer’s treatments have targeted Aβ. However, many of these treatments have failed in clinical trials, leading to questions about this approach.

Aβ is created from a larger protein called amyloid precursor protein through a series of steps involving different enzymes. Normally, APP is processed in a way that prevents the formation of Aβ. However, under certain conditions, the enzymes BACE1 and γ-secretase cut APP in a way that produces Aβ. Once formed, Aβ needs to be cleared from the brain to prevent harmful buildup.

Aβ clearance involves several pathways, including enzyme degradation, transport across the blood-brain barrier, and removal through the brain’s fluid drainage systems. The blood-brain barrier is a network of cells that controls what enters and leaves the brain. Specific proteins help move Aβ out of the brain, but for those with Alzheimer’s, these proteins don’t work as well, leading to Aβ accumulation.

Genetic studies show that Aβ buildup plays a significant role in the disease. For example, people with Down syndrome, who have an extra copy of the APP gene, often develop Alzheimer’s. Mutations in genes related to APP processing can also cause early-onset Alzheimer’s, while certain mutations can protect against it. Both genetic and lifestyle factors, like diabetes and lack of exercise, can increase Aβ production or hinder its clearance.

Despite setbacks, there are promising developments in Aβ-based therapies. Aducanumab, an antibody that targets Aβ, was approved by the FDA for its ability to reduce Aβ plaques in early Alzheimer’s patients. Another antibody, donanemab, has shown even better results in clearing Aβ from the brain. Similarly, lecanemab, which targets soluble forms of Aβ, has been shown to reduce amyloid levels and improve cognitive function. Another drug, Anavex 2-73 (blarcamesine), has shown potential in reducing Alzheimer’s symptoms and brain changes in animal studies and a late stage human trial.

Blarcamesine is a formulation of Anavex, a clinical-stage biopharmaceutical company that develops therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease and other central nervous system disorders. These advances offer new hope that targeting Aβ could still be a valid approach to treating Alzheimer’s.

Understanding Alzheimer’s Disease: Key Findings and Theories

IIn 1992, researchers John Hardy and Gerald Higgins proposed the amyloid cascade hypothesis, which suggests that buildup of Aβ in the brain starts a chain reaction that leads to Alzheimer’s. This chain reaction includes the formation of tau tangles, loss of brain cells, and cognitive decline. This dynamic was prominently featured in a preclinical trial conducted by Anavex.

Since then, many studies have supported this hypothesis. Those include the studies that made the connection between Alzheimer’s and those with Down syndrome, who have an extra copy of the APP gene. Mutations in the APP gene also result in more Aβ, causing early-onset Alzheimer’s. Moreover, certain genetic factors like the apolipoprotein E and clusterin  genes affect how Aβ is managed in the brain, influencing the risk of developing late-onset Alzheimer’s.

How Amyloid Beta Aggregates Form

After being released, Aβ proteins first form various soluble clusters, which then reshape into fibrous structures called plaques. There are two types of plaques: classical and diffuse. Classical plaques have a dense core surrounded by a clear area and an outer layer that includes damaged brain cells and supportive glial cells. Diffuse plaques are scattered and not as dense. Recent studies indicate that classical plaques, which involve inflammatory cells, are more closely linked to cognitive decline in Alzheimer’s patients.

The amyloid cascade hypothesis has evolved over time. Initially, it emphasized large Aβ fibers as the main cause of brain cell damage. However, more recent research suggests that smaller Aβ clusters, called oligomers, are also highly toxic and play a significant role in the disease.

Interaction with Cell Membranes

Amyloid beta aggregates can disrupt cell membranes by forming channels that allow calcium to enter the cell, which can inhibit essential brain functions and lead to cell death. Aβ oligomers can bind to certain molecules on the cell surface, contributing to these harmful effects. Additionally, cholesterol-rich areas in cell membranes facilitate Aβ formation and its interaction with the membrane. Reducing cholesterol levels in cells has been shown to lessen Aβ aggregation and its toxicity in animal models.

One of the early signs of Alzheimer’s is the loss of synapses, the connections between brain cells, which correlates with cognitive decline. Aβ oligomers can alter the shape and density of synapses, impairing their function. They interfere with key receptors involved in synaptic plasticity, such as NMDA and AMPA receptors, leading to disrupted signaling and synaptic loss. Moreover, Aβ-induced changes in tau protein can further damage synapses and contribute to cognitive deficits.

Besides Aβ plaques, neurofibrillary tangles made of tau protein are another key feature of Alzheimer’s. Research conducted by companies like Anavex has shown that Aβ can trigger tau hyperphosphorylation (excessive addition of phosphate groups), which leads to tau tangles and further neuronal damage. In turn, these tau changes can exacerbate the harmful effects of Aβ. Inhibiting certain enzymes that modify tau has been found to reduce tau pathology and improve cognitive function in experimental models.

Alzheimer’s-Related Inflammation and Anavex 3-71

Chronic inflammation in the brain, driven by activated glial cells like microglia and astrocytes, plays a significant role in Alzheimer’s disease. Aβ aggregates can stimulate these cells to release pro-inflammatory substances, contributing to the progression of the disease. Long-term use of anti-inflammatory drugs has been linked to a lower risk of developing Alzheimer’s, suggesting that targeting inflammation could be a potential therapeutic approach.

Recently, Anavex reported that treatment with Anavex 3-71 significantly reduced inflammation, as well as fully reversing cognitive deficits and amyloid pathology in transgenic McGill rats with a late-stage of Alzheimer’s disease-like pathology.

Mitochondrial Dysfunction and Oxidative Stress

Mitochondria, the energy producers of cells, are disrupted in Alzheimer’s, leading to impaired energy production and increased oxidative stress. Amyloid beta oligomers disturb the balance between mitochondrial fission and fusion, causing mitochondrial dysfunction. Additionally, Aβ can impair the import of proteins into mitochondria, further compromising their function. Oxidative stress, resulting from excessive production of reactive oxygen species, contributes to neuronal damage and Aβ production, creating a vicious cycle.

Changes in Neurochemical Systems

Amyloid beta aggregates interact with neurotransmitter systems, particularly glutamatergic signaling, impairing synaptic plasticity and contributing to cognitive decline. They disrupt the balance between long-term potentiation and long-term depression, essential processes for learning and memory. Amyloid beta also affects other neurotransmitter systems, such as the cholinergic system, which is one of the first to degenerate in Alzheimer’s, further impacting cognitive functions.

Impaired Brain Networks

Functional connectivity within brain networks, such as the default mode network and the salience network, is disrupted in Alzheimer’s. These networks are crucial for various cognitive functions, including memory and attention. Reduced connectivity in these networks, observed in both human patients and animal models, is associated with Aβ accumulation and brain atrophy, contributing to the cognitive deficits seen in Alzheimer’s disease.

Understanding these various aspects of Alzheimer’s disease helps researchers at Anavex develop better diagnostic tools and treatments to combat this debilitating condition.

Alzheimer’s Disease Research: Making Sense of New Developments

Research into Alzheimer’s disease often focuses on amyloid beta proteins. These play a key role in the disease and have been widely studied by Anavex and other interests. Scientists measure these proteins to help make an early diagnosis. Typically, Aβ is measured in the cerebrospinal fluid or through brain scans using special imaging techniques like PET scans.

In cerebrospinal fluid tests, low levels of Aβ 42, a specific form of Aβ, can indicate early Alzheimer’s. PET scans look for amyloid plaques in the brain using tracers like 11C-Pittsburgh compound B and others, which show increased amyloid retention. These methods are effective but can be expensive and invasive.

Due to these challenges, researchers are now exploring blood tests as a more accessible way to detect Alzheimer’s. Recent studies have shown that blood levels of certain Aβ proteins and their ratios can reflect brain amyloid status, offering a promising approach for early diagnosis. For example, reduced levels of a protein fragment called sAPPβ in the blood are linked to Alzheimer’s.

Advances in Anti-Amyloid Beta Therapies

To date, five drugs are approved for treating Alzheimer’s, but they mainly address symptoms rather than the underlying disease. These include four cholinesterase inhibitors (donepezil, rivastigmine, and galantamine, with tacrine no longer in use due to liver toxicity) and one NMDA receptor antagonist (memantine).

Researchers are working on new treatments targeting Aβ. Out of 298 therapies in clinical trials, 76 focus on Aβ. These therapies aim to reduce Aβ production, enhance its clearance, neutralize its toxicity, or prevent its aggregation.

BACE1 Inhibitors

BACE1 is an enzyme crucial for Aβ production. Inhibitors of BACE1, like LY2886721, have shown promise in early trials by reducing Aβ levels. However, many have faced setbacks due to side effects or lack of efficacy. Challenges include ensuring the inhibitors specifically target BACE1 without affecting similar enzymes.

Y-Secretase Inhibitors and Modulators

Y-secretase inhibitors can block Aβ production but often cause side effects by interfering with other essential proteins. Newer approaches, such as γ-secretase modulators, aim to selectively reduce toxic Aβ forms while avoiding these issues. However, many candidates have not succeeded in clinical trials.

Immunotherapy

Immunotherapy is a promising strategy, using vaccines or antibodies to reduce brain Aβ. Early vaccines like AN1792 showed potential, but were halted due to side effects. Newer vaccines and antibody treatments, such as aducanumab and lecanemab, are in various trial stages. Aducanumab, for example, was the first Food and Drug Administration-approved therapy targeting Aβ aggregates, but it remains controversial due to mixed efficacy results.

Alzheimer’s Disease Study: A Simplified Overview

Alzheimer’s research is progressing, with significant efforts to develop effective diagnostics and treatments. Blood-based biomarkers and innovative therapies targeting Aβ are at the forefront, offering hope for early detection and better management of the disease. While challenges remain, ongoing studies and trials continue to provide valuable insights and potential breakthroughs in the fight against Alzheimer’s.

The Role of Soluble Amyloid Beta in the Brain

Amyloid beta peptides are found in both the brain and blood throughout a person’s life. While Aβ aggregates are known to be harmful, soluble Aβ at normal levels helps with several important functions like improving brain recovery from injuries, fighting infections, reducing oxidative stress, and even suppressing tumors.

When developing treatments to lower Aβ levels for Alzheimer’s, it’s crucial to target the harmful forms (aggregates) without affecting the beneficial soluble Aβ monomers.

Normal levels of Aβ are vital for maintaining synaptic function and memory. Although Aβ aggregates can harm synapses, low levels of Aβ peptides help protect neurons and stimulate key proteins that support brain functions. Removing Aβ entirely can impair memory, indicating that Aβ monomers are essential for healthy brain activity.

Research suggests that Aβ also plays a protective role in brain injury recovery. After a brain injury, Aβ levels can spike, helping the brain recover. For example, increasing Aβ levels in mice with brain injuries improved their motor memory. Conversely, reducing Aβ levels hindered recovery.

Aβ also acts as an antimicrobial agent. Studies show that Aβ can trap and neutralize various bacteria and viruses, which may explain why the brains of those with Alzheimer’s show higher antimicrobial activity. Aβ can help the immune system fight infections by binding to and neutralizing harmful microbes.

Alzheimer’s patients have lower rates of several cancers. Aβ has been found to inhibit tumor growth by promoting cell death in cancer cells. This antitumor effect is likely due to Aβ’s ability to induce oxidative stress and apoptosis (programmed cell death) in cancer cells.

Aβ peptides at normal levels also can act as antioxidants, protecting cells from oxidative damage. They help prevent the oxidation of lipoproteins in the brain and blood, which is crucial for cellular health.

Aβ also plays a role in neurogenesis (growth of new brain cells). It helps neural progenitor cells differentiate into neurons and glial cells, supporting brain health and function.

The blood-brain barrier protects the brain from harmful substances. Low levels of Aβ help maintain the blood-brain barrier’s integrity, acting like a seal to prevent leakage and inflammation after injuries.

Limitations of Current Therapies

The following are some of the primary issues that limit the current therapies for treating Alzheimer’s, while underscoring the need for further research and development of new therapeutics.

Lack of specificity. Current inhibitors targeting Aβ production can affect other essential proteins, leading to toxicity. For example, γ-secretase inhibitors need to be selective to avoid disrupting Notch-1 signaling, which is crucial for cell communication.

Inaccurate animal models. Most animal models represent the rare genetic form of Alzheimer’s disease, not the more common late-onset form influenced by aging and lifestyle. Better models are needed to mimic the complex nature of sporadic Alzheimer’s.

Delayed application. Aβ therapies are often applied too late, as Aβ accumulation starts many years before symptoms appear. Preventive treatments might be more effective. Early detection through biomarkers and imaging can help identify individuals at risk long before symptoms develop.

Future Directions in Alzheimer’s Disease Research

Anavex Life Sciences continues to explore more precise treatments targeting the harmful Aβ aggregates while preserving beneficial Aβ functions. Preventive strategies and early detection are essential for better managing Alzheimer’s and improving patient outcomes.

Despite setbacks in Alzheimer’s drug trials, Anavex has gained valuable insights. These lessons are crucial for improving the understanding of the disease and development of better treatments. The following are some promising strategies for future drug development:

Combination Therapy and Targeted Approaches

Many current treatments aim to reduce the production of Aβ. However, these treatments haven’t been able to remove existing Aβ plaques or reverse the damage they cause. Combining multiple therapies might be more effective. For example, drugs targeting both Aβ and another protein called tau, which also contributes to Alzheimer’s, could be beneficial. Antioxidants like lipoic acid, vitamin E, and vitamin C might also help by reducing oxidative damage in the brain.

Aβ affects the connections between nerve cells, leading to cognitive decline. Targeting these synaptic issues could be another effective treatment strategy. Overall, a combination of treatments addressing various aspects of Alzheimer’s could be more successful than focusing on a single factor.

Understanding Upstream Problems

Alzheimer’s might result from issues like poor blood flow in the brain, problems with glucose metabolism, cell cycle disruptions, and inflammation. Another process called autophagy, which helps clear out damaged proteins and cell parts, is also crucial. Problems with autophagy can lead to the buildup of toxic proteins like Aβ. Enhancing autophagy might help reduce Aβ levels and improve brain health. For example, rapamycin, a drug that activates autophagy, has shown promise in reducing Aβ plaques and improving memory in animal studies.

Mechanism-Based Therapies

Treatments targeting the early stages of Alzheimer’s might work best if started before symptoms appear. Traditional Chinese medicine, which uses natural products with multiple effects and few side effects, might offer preventive and therapeutic benefits. Compounds from traditional Chinese medicine like morroniside, rutin, and resveratrol have shown potential in treating Alzheimer’s.

Patient-Based Research Models

Using three-dimensional brain organoids, grown from human stem cells, researchers can better model Alzheimer’s. These mini-brains can mimic many features of the human brain, including the blood-brain barrier and connections with other organs. This makes them a powerful tool for studying the disease and testing new treatments. Transplanting these organoids might even help repair brain damage in Alzheimer’s patients. However, current models can only be grown for six months before they start to deteriorate. Developing organoids with their own blood vessels could help them survive longer and more accurately replicate the aging brain.

Identifying Early Biomarkers

Finding biomarkers that can detect Alzheimer’s early is crucial for developing effective treatments. Besides the usual suspects like Aβ and tau, other molecules involved in inflammation and nerve cell connections could serve as early indicators.

For instance, higher levels of progranulin, a growth factor, have been found in people years before Alzheimer’s symptoms appear. Similarly, neurogranin, a protein linked to nerve cell function, is elevated in early Alzheimer’s and can predict cognitive decline.

MicroRNAs, small RNA molecules that regulate gene expression, are also being studied as potential biomarkers. They are easily detectable in body fluids and are involved in Alzheimer’s development. Additionally, eye health and mental health conditions like depression might provide early clues about Alzheimer’s risk.

Aβ remains a key target for Anavex and other organizations focused on Alzheimer’s research, despite past failures in drug trials. Understanding why these trials failed will help design better treatments. Early detection through biomarkers and more accurate models of the disease are essential.

Combination therapies that target multiple disease processes and are tailored to individual patients hold promise for more effective treatment. These strategies could pave the way for more successful Alzheimer’s therapies in the future.

 

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Last Updated on August 29, 2024 by Marie Benz MD FAAD