Alzheimer’s disease (AD) is a neurodegenerative disease, the most common cause of dementia in senile population. According to the World Health Organization, AD represents around 12% of people over 65 worldwide. Due to its etiological agents, neurofibrillary tangles (NFT) and amyloid plaques (AP), several attempts to explain the genesis and progression of AD have been proposed. Pathological variants of tau protein, are the main precursor for AD onset, with a molecular mechanism based on neuroinflammatory processes in the context of the neuroimmunomodulation theory. Microglial cells play preponderant roles in innate immunity and are the main source of proinflammatory factors in the central nervous system (CNS), the links between microglia and neurons are the main focus on AD pathogenesis. Depending on these factors, either a neuroprotective or a proinflammatory effect could be triggered. In AD, a persistently active microglial condition generates neuronal damage and death, causing the release of pathological tau toward the extracellular environment. This causes the activation of microglia, promoting a feedback mechanism and generating a continuous cellular damage. After activation of microglia, generation of NF‐kB occurs, thus promoting the expression and release of proinflammatory cytokines. As a consequence, short‐lived cytotoxic factors, such as O2, NO and other reactive oxygen species, are released. In normal physiological conditions, tau’s kinases play a role in regulating normal tau functions in neurons. Glycogen synthase kinase 3‐beta (GSK3β)‐mediated tau phosphorylation promotes N‐methyl‐D aspartate receptor (NMDAr)‐mediated long‐term depression. The increase of proinflammatory cytokines during AD by microglia leads to an increase in kinase expression and activity of cyclin‐dependent kinase 5 (Cdk‐5) and GSK3‐β. On the other hand, TNF‐α and IL‐8 increase expression and activity of Cdk5, whereas IL‐1β hyperactivates GSK3‐β, leading to tau hyperphosphorylation and impairing its normal function. Tau hyperphosphorylation results in microtubule destabilization, impaired axonal transport, NMDAr‐mediated neurotoxicity, synaptic dysfunction and cell death. Finally, the previously summarized mechanisms could explain the onset and progression of AD, opening a new projection to focus research on therapeutic agents that could modulate the interactions between tau and microglial cells. The neuroimmunomodulation mechanism has been the conceptual framework for the search of therapeutic approaches for AD and other neurodegenerative disorders.
Part of the book: Mechanisms of Neuroinflammation