Lifeboat Foundation

Novo Nordisk’s recent growth renaissance has arrived thanks in no small part to semaglutide—the GLP-1 molecule behind the company’s leading marketed trio of Ozempic, Rybelsus and Wegovy.

These days, much of the semaglutide hype surrounds Ozempic’s domination in diabetes, plus Wegovy’s potential to stir the slumbering giant that is the global obesity market. But even as the molecule’s metabolic empire prospers, Novo Nordisk isn’t letting its GLP-1 stay in its comfort zone. Novo is also pitting the drug against a pair of elusive targets: nonalcoholic steatohepatitis (NASH) and Alzheimer’s disease.

And while CEO Lars Fruergaard Jørgensen is quick to admit the company’s ambitions in these new diseases are among Novo’s “most risky” R&D endeavors, the payoff for patients could be “tremendous,” he said during a recent interview at Novo Nordisk’s headquarters in Plainsboro, New Jersey.

The promising results led to improved not only cognitive function but also brain connectivity.

An Inserm team at the Lille Neuroscience & Cognition laboratory is working with scientists at Lausanne University Hospital to evaluate the effectiveness of GnRH injection therapy in enhancing cognitive functions in a small group of Down syndrome patients, according to a press release published on Eurekalert.

Down syndrome is the most common chromosomal condition in the United States. According to the Centers for Disease Control and Prevention, about one in every 6,000 babies born in the U.S. has Down syndrome. It causes various symptoms, such as deterioration in cognitive capacity.

Negative symptoms are complex psychopathology. Although evidence generally supported the NIMH five consensus domains, research seldom examined measurement invariance of this model, and domain-specific correspondence across multiple scales. This study aimed to examine the interrelationship between negative symptom domains captured by different rating scales, and to examine the domain-specific correspondence across multiple scales. We administered the Brief Negative Symptom Scale (BNSS), the Self-evaluation of Negative Symptoms (SNS), and the Scale for Assessment of Negative Symptoms (SANS) to 204 individuals with schizophrenia. We used network analysis to examine the interrelationship between negative symptom domains.

Summary: Fentanyl exposure produces specific EEG signatures in the brain. The findings also revealed the drug impairs people’s breathing four minutes before noticeable changes in alertness.

Source: Mass General.

Fentanyl is used to supplement sedation and to relieve severe pain during and after surgery, but it’s also one of the deadliest drugs of the opioid epidemic.

Summary: A new study reveals a genetic link between Alzheimer’s disease and several gut-related disorders. Researchers report Alzheimer’s patients and those with intestinal disorders have specific genes in common. The findings add to the evidence the gut-brain axis may play a role in the development of neurodegenerative disorders.

Source: Edith Cowan University.

People with gut disorders may be at greater risk of developing Alzheimer’s Disease (AD).

Summary: Study reveals a novel mechanism in locus coeruleus neurons caused by the loss of the GPT2 mitochondrial enzyme that is implicated in the development and progression of neurodegenerative diseases.

Source: Brown University.

The locus coeruleus is among the first brain regions to degenerate in Alzheimer’s and Parkinson’s disease, physicians and scientists have known. But why this area is so vulnerable is less understood.

Summary: A 20-minute session of non-invasive brain stimulation over four days helps to improve both working and long-term memory in those aged 65 and older.

Source: Boston University.

According to the Alzheimer’s Association, an estimated 6.5 million Americans aged 65 and older are living with Alzheimer’s in 2022. That figure is predicted to nearly double by 2050.

Electrical activity in neurons is highly energy demanding and accompanied by rises in cytosolic Ca²⁺. Cytosolic Ca²⁺, in turn, secures energy supply by pushing mitochondrial metabolism either through augmented NADH transfer into mitochondria via the malate aspartate shuttle (MAS) or via direct activation of dehydrogenases of the TCA cycle after passing into the matrix through the mitochondrial Ca²⁺ uniporter (MCU). Another Ca²⁺-sensitive booster of mitochondrial ATP synthesis is the glycerol-3-phosphate shuttle (G3PS) whose role in neuronal energy supply has remained elusive. Essential components of G3PS are expressed in hippocampal neurons. Single neuron metabolic measurements in primary hippocampal cultures derived from rat pups of either sex reveal only moderate, if any, constitutive activity of G3PS. However, during electrical activity neurons fully rely on G3PS when MAS and MCU are unavailable. Under these conditions, G3PS is required for appropriate action potential firing. Accordingly, G3PS safeguards metabolic flexibility of neurons to cope with energy demands of electrical signaling.

SIGNIFICANCE STATEMENT:

Ca²⁺ ions are known to provide a link between the energy-demanding electrical activity and an adequate ATP supply in neurons. To do so, Ca²⁺ acts both, from outside and inside of the mitochondrial inner membrane. Neuronal function critically depend on this regulation and its defects are often found in various neurological disorders. Although interest in neuronal metabolism increases, many aspects thereof have remained unresolved. In particular, a Ca²⁺-sensitive NADH shuttling system, the glycerol-3-phosphate shuttle, has been largely ignored with respect to its function in neurons. Our results demonstrate that this shuttle is functional in hippocampal neurons and safeguards ATP supply and appropriate action potential firing when malate aspartate shuttle and mitochondrial Ca²⁺ uniporter are unavailable, thereby ensuring neuronal metabolic flexibility.

Lecture from the mini-series “Cosmology & Quantum Foundations” from the “Philosophy of Cosmology” project. A University of Oxford and Cambridge Collaboration.