Characterization of neutrophil sub-populations in i) mouse models of AD-like disease and ii) subjects with cognitive impairment and an AD diagnosis at the level of neuropsychological testing.
Recent reports showed that neutrophils could differ in morphology and function, ranging from an inflammatory to a suppressive phenotype, underlining that their state of differentiation or activation may be context-dependent, which includes the tissue environment, the trigger of the inflammatory response, and other cell types interacting with them. Altogether these factors determine whether an inflammatory response is a positive feedback amplification progress or a negative feedback self-limiting progress.
Our current knowledge about neutrophil heterogeneity, the detection of hallmark effects, and the detection of critical mediators that trigger the conversion from physiological tissue repair and regeneration to pathological tissue damage are still largely unknown.
Study the mechanistic basis of host-microbiota interactions in rodent AD models, and evaluate the translational potential of our pre-clinical findings to elderly humans with cognitive impairment.
A growing area of research in the pathophysiology of neurodegenerative diseases is the gut microbiome, which comprises a complex community of commensal microorganisms.
New research indicates that an imbalance in the bacteria in the gut (known as gut dysbiosis) may be the connection between inflammageing and the symptoms of Alzheimer's disease. The gut microbes found in the faces and mucus of individuals with Alzheimer's disease are different from those found in healthy individuals. Comparing germ-free animals to those exposed to various bacteria, probiotics, or antibiotics suggests that the gut microbiome is linked to cognitive function and the development of Alzheimer's disease. Interestingly, studies have shown that gastrointestinal issues often occur before neurodegenerative symptoms, such as motor deficits in individuals with Parkinson's disease.
During the onset of Alzheimer's disease in a mouse model, the enteric nervous system (ENS) undergoes significant changes. This is because the same neurodegenerative processes that affect the brain also occur in the gut, leading to functional gastrointestinal abnormalities.
The communication between the gut microbiota and the brain, known as the "microbiota-gut-brain axis," involves various pathways such as the vagus nerve, neuroendocrine pathways, bacteria-derived metabolites, and systemic immunity. Indirectly, the gut microbiome communicates via gut-derived molecules that trigger inflammation in the nervous system, which can induce neurological symptoms.
Recent studies have shown that circulating leukocytes migrate into the brain, promoting memory decline and neuroinflammation. This suggests that gut microbiota products activate peripheral immune system cells, which play a critical role in Alzheimer's disease. However, the molecular mechanisms underlying the relationship between these metabolites and immune cells are still unclear.
Characterization of neutrophils interactions with CNS-resident cells in the spinal cord of EAE mice.
The neutrophil has been unmasked as a new player in autoimmune demyelination, but still, their phenotype and functions are largely unknown. Multiple studies in animal models of experimental autoimmune encephalomyelitis (EAE), which mimics MS's autoimmune component, confirmed neutrophils' pathogenic role.
However, the mechanisms involved in neutrophil transmigration, accumulation, movement inside the CNS parenchyma, and interaction with CNS-resident cells during EAE are mainly unknown.
Over the past few years, Dr. Zenaro has dedicated her research to studying the role of neutrophils and gamma-delta T cells in Alzheimer's disease. Additionally, she is partnering with other experts to explore the importance of brain barriers and the connection between the brain and peripheral systems, like the gut-brain axis, in the neuroimmunology of neurodegenerative disorders.