Neuroscientists at King’s College London have pinpointed a mechanism behind the increased neural connectivity observed in the very early stages of Alzheimer’s disease. Published in Translational Psychiatry, the study also demonstrated that a cancer medication has the potential to reduce this hyperconnectivity.

The research showed that low levels of the protein amyloid-beta could induce hyperconnectivity and this pattern closely resembled changes seen in the brains of people with mild cognitive impairment (MCI). Amyloid-beta is thought to be instrumental in Alzheimer’s disease, where it creates plaques—or sticky clumps of amyloid-beta proteins—around the neurons.

These new findings suggest that low levels of amyloid-beta alone are enough to trigger early, disease-relevant changes in how brain cells connect.

Here, we show that pharmacologic restoration of NAD⁺ homeostasis via P7C3-A20, a neuroprotective compound that restores NAD⁺ homeostasis without producing supraphysiologic NAD⁺ levels,^{51,52,53,54,55,56} reverses cognitive deficits and neuropathology in advanced Aβ- and tau-driven AD models. We identify conserved molecular signatures between human and mouse AD and show that the magnitude of NAD⁺ homeostasis disruption correlates with pathology and symptom severity in mouse and human AD. We also demonstrate that NDAN brains display transcriptional profiles compatible with preserved NAD⁺ homeostasis and that P7C3-A230 restores NAD⁺ homeostasis and prevents oxidative damage and mitochondrial dysfunction in oxidatively stressed human brain microvascular endothelial cells (HBMVECs), a key component of the BBB. We additionally identify 46 conserved protein alterations in human and mouse AD brain that are corrected by AD reversal, together with overlapping transcriptomic changes in human AD. This highlights potential mechanisms and therapeutic targets for preserving and restoring brain resilience to AD.

These findings of cognitive recovery and pathological reversal in diverse models of advanced AD support disease progression as modifiable and driven by diminished brain resilience, with early cognitive impairment resulting from processes that promote neurodegeneration rather than solely from fixed neuronal loss. We propose that therapies to restore brain resilience, such as normalization of NAD⁺ homeostasis, merit clinical evaluation for prevention and reversal of AD and related dementias.

Combined metabolic activators to treat mitochondrial dysfunction.

Mitochondrial dysfunction is a common feature of many human diseases and is emerging as a therapeutic target.

Systems biology and multiomics approaches have revealed that deficits in glutathione and NAD+ metabolism, impaired fatty acid oxidation, and disrupted redox balance are key drivers of disease pathogenesis.

Combined metabolic activators (CMA) were developed to address these metabolic deficits through the complementary actions of serine, Nacetylcysteine, L-carnitine, and NAD+ precursors.

CMA have been shown to lower hepatic fat, reduce systemic inflammation, accelerate recovery from infection, and improve cognitive performance in clinical studies. sciencenewshighlights ScienceMission https://sciencemission.com/Targeting-mitochondrial-metabolism

Mitochondria play a central role in energy metabolism, redox balance, and cellular homeostasis, and their dysfunction has been implicated in the pathogenesis of complex human diseases. Advances in systems biology and omics technologies have elucidated the mechanisms underlying these conditions, including metabolic dysfunction, mitochondrial impairment, inflammation, and redox imbalance. Preclinical and early clinical studies of combined metabolic activators (CMA), a formulation of bioactive metabolites, have demonstrated improvements in mitochondrial function and systemic metabolic profiles across multiple diseases.

A simple cheek swab could one day provide a quick and noninvasive diagnostic test for schizophrenia. A new study published in Science Advances has identified higher levels of two biological markers in the cheek swabs of patients with schizophrenia compared with people who don’t have this mental health disorder. Schizophrenia is a long-term condition with a range of symptoms including hallucinations, delusions, muddled thoughts and loss of interest in everyday activities.

There is no single test for the illness, and diagnosis can be challenging because symptoms vary widely between people and typically relies on observing a patient’s behavior. It can, therefore, sometimes take months for a professional to make a diagnosis with any degree of certainty, as they have to rule out other possible causes. That is a lot of time for someone to wait without the right treatment if it is needed.

So researchers led by a team at Rutgers University in New Jersey decided to investigate whether molecular signatures in easy-to-collect buccal (cheek) cells could serve as reliable biomarkers.

Researchers use single-cell analysis to show how transplanted neural stem cells interact with the retina to preserve vision in retinitis pigmentosa.