As noted by the authors of today's open access review paper, Alzheimer's disease is just as strongly characterized by chronic inflammation in brain tissue as it is by the presence of aggregates of amyloid-β and phosphorylated tau. More modern views of Alzheimer's disease etiology place more emphasis on chronic inflammation as a cause of pathology, either wrapping it into the amyloid cascade hypothesis, or replacing amyloid-β with inflammatory processes in the progression of the foundational, earlier stage of the condition.
The infection-senescence hypothesis, for example, suggests that persistent infection leads to cellular senescence in the supporting and immune cells of the brain (such as astrocytes and microglia), and senescent cells generate potent inflammatory signals that drive tau aggregation and the consequent widespread death of neurons. This view of senescent cells as agents of inflammation, that in turn provokes tau pathology, is supported by studies involving the use of senolytic therapies to clear senescent cells in the brains of mice engineered to produce tau aggregates. With senolytic treatment, all three metrics of senescent cell burden, chronic inflammation, and tau pathology are markedly reduced in these mouse models of tauopathy.
This sort of specific theorizing and experimentation on neurodegeneration and neuroinflammation is not happening in a vacuum. There is considerable interest in a wide range of strategies that might reduce chronic inflammation in the aging brain, and thereby slow or reverse the progression of neurodegenerative conditions. The evidence to date from work on senolytics suggests that some fraction of the declines of old age are actively maintained by inflammatory signaling, and reverse themselves quite rapidly when that signaling is suppressed (such as by removal of senescent cells). The situation in the brain may be much the same as that elsewhere in the body, even accounting for the poor regenerative capacity of central nervous system tissue.
Neuroinflammation is a process regulated by brain resident macrophages, the microglia cells, which are required to recognize and eliminate any toxic component in the central nervous system (CNS). Microglia has a high capacity for mobility, and they can switch between two different phenotypes, M1 and M2, characterized by a different morphology and cytokine profile. The M2 phenotype is the resting type that actively monitors the brain in healthy conditions. The switch to M1 begins with the recognition of the pathogen-associated molecular patterns (PAMPs) or the damage-associated molecular patterns (DAMPS) by the pattern recognition receptors (PRRs).
Pro-inflammatory cytokines purpose is to orchestrate the neutralization and elimination of toxic molecules and/or cellular debris. In normal conditions, once the toxic stimuli have been cleared, microglia swifts to the anti-inflammatory (M1) phenotype and secretes anti-inflammatory cytokines, brain-derived neurotrophic factor (BDNF), or nerve growth factor (NGF), whose role is to terminate the innate immune response and contribute to restore the synaptic function. However, under pathological conditions, microglia cells do not go back to their resting state, thus causing a chronic inflammation process, with the overproduction of pro-inflammatory cytokines and reduction of neuroprotective factors that in sustained situations become highly toxic, leading to neurodegeneration. Therefore, the chronic neuroimmune system activation underlies the initiation and progression in many dementias, and surely, is involved in the late onset of AD. Not only amyloid-β activates the microglia, but also misfolded Tau interaction with microglia triggers inflammation.
Neuroinflammation and insulin resistance are considered major neuropathological events underlying the onset and progression of AD; therefore, multiple strategies that target these processes have been developed to effectively treat this disease. In the current review, we have revised some of the latest preclinical and clinical studies targeting inflammation in AD, either directly with anti-inflammatory drugs or indirectly, improving insulin signaling. Taking together all clinical studies revised, we conclude that strategies targeting neuroinflammation together with insulin resistance have, finally, demonstrated to be a promising therapeutic potential in Alzheimer's disease, especially at early stages. However, many molecules have produced inconclusive results, and other methods, such as promoting neuroprotection via CB2 boosting or restoring a more youthful gut microbiome, are still at the preclinical stage. In addition, patient's stratification seems to be crucial to determine best treatment. The definite cure for AD does not exist yet; however, targeting neuroinflammation may be a path worth pursuing.