Combatting Neurodegeneration: From Single Receptors to Whole-Body Biology
From targeting individual receptors to taking a systems-level approach, researchers hope to uncover novel therapies.
Neurodegenerative disorders are chronic conditions characterized by progressive neuronal dysfunction and death.
Many conditions, from dementias to Parkinsonism-type and motor neuron diseases, fall under this umbrella term. While each has a distinct pathophysiology, they are united by their ability to significantly alter, and often derail, the lives of those living with them, as well as the loved ones who care for them.
As neurodegenerative diseases progress, individuals may experience declines in physical and cognitive function, limiting anything from their ability to carry out everyday tasks to recalling the memories that make up who they are.
While drugs have proven successful in managing symptoms, researchers are yet to truly uncover the root causes of many of these conditions—an endeavor that could enable us to halt, reverse, or even prevent neurodegenerative disease altogether.
Two experts in the field are working to achieve just this: Dr. Ahmed El-Yazbi, professor and director of the Research and Innovation Hub at Alamein International University, and Dr. Khaled Abdelrahman, assistant professor at The University of British Columbia. Together, their work spans neurodegeneration, cardiometabolic biology, and pharmacology.
Ahead of their discussion on neurodegenerative disease therapies at the American Society for Pharmacology and Experimental Therapeutics (ASPET) conference, Abdelrahman and El-Yazbi shared their insights with Technology Networks. They reflected on what drew them to the field, why a systems-level perspective is essential to understanding neurobiology, and therapeutic strategies currently being investigated to target neurodegeneration—the old and the new.
What motivates researchers to pursue neurodegenerative disease research?
For Abdelrahman, the recognition of persistent knowledge gaps—alongside a growing disease burden—spurred his desire to enter the space. “I felt the field still had a lot of unanswered questions,” he explained. “To me, that wasn’t discouraging: it was indeed motivating.”
“It felt like an opportunity to approach the problem from a different angle, focusing on underlying mechanisms and helping bridge critical gaps in a way that could genuinely move discoveries toward translation.” — Dr. Khaled Abdelrahman
Meanwhile, El-Yazbi’s path was steered by findings during his postdoctoral work. Upon realizing the link between systemic cardiometabolic impairments and cerebrovascular dysfunction, he set out to study their shared mechanisms. In his words: “You see the same underlying dysfunctions—endothelial impairment, inflammation, altered energy handling—playing out across organs. Over time, I became more interested in targeting those shared mechanisms pharmacologically rather than studying them in isolation.”
Drivers of neurodegenerative research:
- Gaps in research may attract researchers to disciplines, rather than demotivate them.
- Cross-disciplinary work is especially valuable, as researchers increasingly uncover overlap between disease pathophysiology.
- The potential to translate findings into pharmacology, and subsequently therapeutics, motivates individuals to pursue neurodegenerative research.
The overlap between systemic metabolic dysfunction and neurodegeneration
Metabolism refers to the set of chemical processes that sustain life. Whether it’s turning food into energy, maintaining tissues, or removing waste, our metabolism keeps the body functioning.
When these processes are not adequately regulated, there can be numerous consequences: insulin resistance, seen in diabetes, elevated “bad” cholesterol, observed in cardiovascular disease, and high blood pressure, associated with adverse cardio- and cerebrovascular events.
El-Yazbi explained how this metabolic dysregulation can impact the brain: “Metabolic dysfunction creates a chronic-stress environment—low-grade inflammation, oxidative stress, vascular impairment—all of which the brain is particularly sensitive to.” He highlighted how these changes impact the microglia—specialized immune cells that reside in the central nervous system—and how this can shift them from a protective state into one that drives neuroinflammation.
Furthermore, El-Yazbi’s research group has demonstrated the role of vascular impairment in neurodegeneration. “Impaired blood flow, due to endothelial dysfunction resulting from metabolic deterioration, creates a state of mild neuronal hypoxia,” he explained.
Neuronal hypoxia
Hypoxia refers to low oxygen levels, while neuronal hypoxia specifically describes low oxygen levels within neurons. Neurons have a high metabolic demand, so even mild reductions in oxygen can disrupt normal cellular function.
El-Yazbi noted that the effect of mild neuronal hypoxia seems to be amplified by insulin resistance, a common consequence of metabolic dysfunction. Together, these changes disrupt neuronal quality control processes and contribute to cell death.
Rather than viewing neurodegeneration as a purely neurological disorder, this perspective also frames it as a downstream consequence of systemic dysfunction.
As populations age, obesity rates continue to rise, and chronic stress becomes the norm, it is anticipated that the number of individuals living with metabolic dysfunction will inevitably grow. In turn, the pool of people susceptible to neurodegenerative changes will increase, highlighting the need for therapeutic strategies.
The link, put simply:
- Metabolic dysfunction contributes to neurodegeneration through inflammation, oxidative stress, and impaired blood flow.
- Impairment of multiple metabolic processes, such as vascular disease occurring alongside insulin resistance, can compound disease progression.
From metabolism to mechanisms for treatment: GPCR signaling in Alzheimer’s disease
Abdelrahman is among the researchers hoping to address the need for novel therapies targeting neurodegeneration. His work centers on G protein-coupled receptors (GPCRs) as key regulators of Alzheimer’s disease biology and how they can be leveraged for therapeutic intervention.
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GPCRs
GCPRs are cell membrane receptors characterized by seven transmembrane domains. They respond to a wide range of external signals, from neurotransmitters to sensory stimuli. Once bound, GPCRs activate an intracellular signaling cascade.
Abdelrahman explained the neurological role of GPCRs: “Many GPCRs play a crucial role in the brain, especially in key processes required for memory formation.” He noted that these same receptors are also implicated in the processing of key proteins implicated in Alzheimer’s disease—amyloid beta and tau.
“When GPCR signaling becomes disrupted, it can affect how the brain communicates, influence the buildup of amyloid beta and tau proteins, and drive inflammation in the brain,” he continued.
“GPCRs are really at the center of both normal brain function and the key pathological changes we see in Alzheimer’s.” — Dr. Khaled Abdelrahman
This centrality underpins their therapeutic appeal. “They have the potential to modify disease progression rather than only address symptoms,” Abdelrahman explained. Additionally, they offer pharmacological versatility, with activation, inhibition, and pathway-specific modulation all on the cards.
Notably, recent findings from Abdelrahman’s group also suggest that GPCR signaling may be influenced by biological sex, which may offer an explanation for sex-specific Alzheimer’s disease prevalence.
GPCRs as a driver and a target in Alzheimer’s disease:
- GPCRs sit at the intersection of normal neuronal function and Alzheimer’s pathology.
- Disrupted GPCR signaling contributes to amyloid and tau build-up within the brain.
- The druggability of GPCRs makes them strong therapeutic candidates.
Something old, something new: Drug repurposing for neurodegenerative diseases
While researchers continue to identify and investigate novel targets and drugs, there is also opportunity to repurpose existing therapies. El-Yazbi emphasized that drug repurposing forms a pragmatic strategy to accelerate drug development.
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In line with his background, he focuses his efforts on agents that simultaneously target metabolic and inflammatory pathways. “We have a particular interest in drugs that modulate both metabolic and inflammatory pathways simultaneously,” he said, highlighting SGLT2 inhibitors, PPAR agonists, and upstream anti-inflammatory agents as promising candidates.
SGLT2 inhibitors and PPAR agonists
SGLT2 inhibitors are a class of antidiabetic drugs. They lower blood glucose by promoting glucose excretion in the urine.
PPAR agonists are used to treat primary biliary cholangitis, a chronic liver disease, and metabolic disorders. They activate receptors regulating gene expression for lipid metabolism, glucose homeostasis, and inflammation.
While the potential to repurpose existing drugs for new indications is exciting, achieving clinical success remains challenging. El-Yazbi cautioned: “Preclinical models don’t fully capture the complexity of human disease.”
Furthermore, while drug repurposing is used as a strategy to efficiently bring new drugs to patients, demonstrating efficacy in new indications still requires scientifically robust and costly clinical trials.
Opportunities and hurdles in drug repurposing:
- Repurposed drugs can target multiple disease mechanisms simultaneously.
- Established safety profiles may accelerate development timelines.
- Translational challenges remain; clinical validation is paramount.
Improving translation to develop neurodegenerative disease therapies
Translating promising insights into reliable clinical outcomes remains a challenge for both novel compounds and drug repurposing alike.
Even when using multi-model approaches to study GPCR targets across in vitro, ex vivo, and in vivo systems, Abdelrahman noted that predicting outcomes remains difficult. Positively, he sees potential for AI tools to overcome this.
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“We see an opportunity for machine learning tools to help integrate large datasets generated from multiomics and functional studies,” he said. These approaches could identify patterns, prioritize targets, and refine the selection of drug candidates earlier in development timelines.
While still in the early stages, Abdelrahman noted that his team is actively exploring these approaches with collaborators, including El-Yazbi.
Combining experimental and computational approaches
- Multi-model experimental strategies are essential for elucidating biological mechanisms.
- AI and machine learning can improve target prioritization.
- Adoption of computational tools earlier in drug development workflows may enhance translational success rates.
Neuroinflammation and neurodegeneration: the questions yet to be answered
Looking ahead, both researchers emphasized the need for a more nuanced understanding of neuroinflammation.
Abdelrahman raised the question of whether neuroinflammation is a driver of disease, a consequence, or a bit of both. At the same time, El-Yazbi highlighted the importance of clarifying when neuroinflammation shifts from a protective to a harmful state. By answering these questions, researchers can advance our understanding of neurodegeneration and develop therapeutic strategies.
El-Yazbi also highlighted the importance of considering systemic health—to target the brain, we likely need to target the body as a whole.
By bringing together metabolic health, pharmacology, and neurobiology, this discussion highlighted current approaches aimed at combatting neurodegenerative disease and the work that remains to be done.
- Neurodegenerative research benefits from a systems-level, whole-body perspective.
- Both novel and repurposed drugs represent promising, mechanistically grounded therapeutic strategies.
- Implementing AI into drug development workflows may be critical to overcoming longstanding translational barriers.
This content includes text that has been created with the assistance of generative AI and has undergone editorial review before publishing. Technology Networks' AI policy can be found here.
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