Neurodegenerative diseases and Neuro-inflammation – translation from rodent to patients?

Neurodegenerative diseases and Neuro-inflammation – translation from rodent to patients?

25 Avr Neurodegenerative diseases and Neuro-inflammation – translation from rodent to patients?

Inflammation and microglial activation is a common component of the pathogenesis for several neurodegenerative diseases, including Alzheimer’s disease or Parkinson’s disease. Microglia, the resident innate immune cells in the brain, actively monitor their environment but can become over-activated in response to diverse cues to produce cytotoxic factors. While this activation is necessary and critical for host defence, too much of it is neurotoxic. Unfortunately, the mechanisms initiating this deleterious neuro-inflammation are poorly understood. The identification of the stimuli and mechanisms responsible for progressive microglial activation and associated neuronal damage is essential to understand the etiology and pathology of neurodegenerative diseases.

A systemic inflammation like the one observed in patients with neurodegenerative diseases can be induced by an intraperitoneal injection of lipopolysaccharide (LPS). This endotoxin from gram-negative bacteria, damages dopaminergic (DA) neurons only in the presence of microglia, and induces cognitive impairment in mice. LPS activation of microglia causes the progressive and cumulative loss of DA neurons over time. Thus, microglia can induce neuron damage, but also become persistently activated to produce continuous neurotoxicity.

In order to discover the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences, researchers gave a single (LPS) or tumour necrosis factor alpha (TNFα) injection to adult wild-type mice and mice lacking TNFα receptors.

They observed that the systemic LPS administration resulted in rapid brain TNFα increase that remained elevated for 10 months, while peripheral TNFα (serum and liver) subsided by 9 h (serum) and 1 week (liver). LPS reduced the number of DA neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. This activation and neuroinflammation therefore persisted long after initial events, and a delayed and progressive loss of DA neurons in the substantia nigra (SN) was observed, similar to Parkinson’s disease.

Both injections activated microglia and increased expression of brain pro-inflammatory factors in wild-type mice, but not those without the TNFα receptor. Meaning that transfer of peripheral inflammation to the brain happens through TNFα.

Therefore, the researchers showed that through TNFα, peripheral inflammation in adult animals can activate brain microglia to produce chronically elevated pro-inflammatory factors and this can induce delayed and progressive loss of DA neurons in the SN. A single occurrence of sepsis and peripheral inflammation could therefore result in self-propelling neuroinflammation and progressive DA neurodegeneration through TNFα.

These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson’s disease.

Syncrosome is an Efficacy Characterization preclinical CRO that offers relevant disease models, cutting-edge techniques and a comprehensive background of physiopathology to assist drug discovery companies. Syncrosome uses LPS-rodent to study neuro-inflammation.


key words: Alzheimer’s disease, preclinical CRO, preclinical study, animal model, animal research, dopaminergic neurons, hippocampus, cerebral cortex, neuroprotection, Alzheimer animal model, LPS, drug, LPS pre-clinical, LPS mice, neuro-inflammation, pathogenesis, cytokines, chemokines, intraperitoneal injection of lipopolysaccharide, Parkinson’s disease

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