Long-term cognition via minimizing neuroinflammation

There is increasing evidence suggesting that chronic neuroinflammation is the most relevant pathological feature of Alzheimer’s disease (AD), regulating other pathological features, such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau. Systemic inflammatory signals caused by systemic disorders are known to strongly influence neuroinflammation as a consequence of microglial activation, inflammatory mediator production, and the recruitment of peripheral immune cells to the brain, resulting in neuronal dysfunction.

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple Sclerosis (MS) are characterized by neuronal degeneration and neuronal death in specific regions of the central nervous system. Neurodegeneration is mediated by inflammatory and neurotoxic mediators. Though inflammation is crucial in the onset and the progression of neurodegenerative diseases, anti-inflammatory drugs do not provide significant therapeutic effects.

It is well known that long-standing inflammation negatively influences the brain over the course of a lifetime due to the senescence of the immune system. In the case of AD, neuroinflammation can be considered part of a characteristic pathological triad involving Aβ plaques and NFTs, with plenty of evidence of an inflammatory response occurring in AD. 

Neuroinflammation is defined as an inflammatory response within the brain or spinal cord. This inflammation is mediated by the production of cytokines, chemokines, reactive oxygen species, and secondary messengers.

Both brain and spinal cord injury involve an acute, beneficial initial inflammatory response which becomes damaging should it persist too long.

Repeated social defeat induces activation of microglia and increased pro-inflammatory cytokine and chemokine expression in the brain. Stress-induced neuropsychiatric disturbances may involve impaired neuroplasticity caused by microglial activation, monocyte recruitment, and enhanced neuroinflammatory signaling.

Both physical and emotional stress is associated with inflammatory cytokine release. Stress can also cause sleep disorders. Since individuals with irregular sleep schedules are more likely to have chronic inflammation than consistent sleepers, sleep disorders are also considered as one of the independent risk factors for chronic inflammation.

Systemic (chronic) inflammation, which leads to neuroinflammation, is likely a risk factor for the progression of neurodegenerative diseases. Chronic neuroinflammation is thought to be a key factor in the progression of neurodegenerative diseases. Age-related senescent inflammation is suspect. One key trigger during aging is changes in the gut, such as the increase in gut permeability and alterations in microbiota composition. Gut dysfunction may be a driver of systemic inflammation, and in turn neuroinflammation. This blog post on chronic inflammation is applicable.

People with irritable bowel syndrome (IBS) are more susceptible to gut hyperpermeability in later life than healthy individuals (26). Interestingly, those with IBS are also more at risk at developing AD, supporting the idea that gut hyperpermeability is a risk factor for AD.  Microbiota dysbiosis proceeds AD development and, therefore, may be a driver in the disease progression.

Some short-chain fatty acids (SCFAs) are known to support intestinal barrier function, and these SCFAs, as well as the microbes that produce them, have been found to be in higher abundance in healthy older adults versus those who are frail or experiencing cognitive impairment. In addition, in older adults with cognitive performance from average to AD, anti-inflammatory SCFA concentrations were positively correlated with cognitive performance; whereas as pro-inflammatory microbial lipopolysaccharide concentrations were associated with poorer cognition. SCFAs downregulate the expression of pro-inflammatory cytokines, such as IL-1β which is associated with not only increased intestinal barrier permeability, but also blood brain barrier permeability and a glial cell inflammatory state.

Sodium butyrate is capable of decreasing microglial activation and pro-inflammatory cytokines secretion. Likewise, acetate treatment of microglia primary culture has been shown to reduce inflammatory signaling.

Cerebrospinal fluid provides immune protection to the brain. As people age, their CSF immune system becomes dysregulated. In cognitively impaired people, inflamed T-cells cloned themselves and flowed into the CSF. These inflamed T-cells can enter the brain and wreak havoc.

High blood sugar can cause neuroinflammation, which can then compromise the blood-brain barrier resulting in cognitive decline.

For those on the autistic spectrum, brain inflammation is likely.

The Ω-3 fatty acids have shown anti-amyloid, anti-tau and anti-inflammatory actions in the brains of animals. Ω-3 fatty acids  are involved in both the reduction in and resolution of inflammation. Docosahexaenoic acid (DHA), the main Ω-3 PUFA in the brain, modulates oxidative reactions and inflammatory cytokine production in microglial and neuronal cells. Docosahexaenoic acid prevents neuroinflammation by inhibiting transcription factor NFkappaB, preventing cytokine secretion, blocking the synthesis of prostaglandins, leukotrienes, and thromboxanes, and modulating leukocyte trafficking.