Central Nervous System Inflammation and Cholesterol Metabolism Alterations in the Pathogenesis of Alzheimer’s Disease and Their Diagnostic and Therapeutic Implications

Abstract

During the last few years, an increasing amount of evidence points to the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration. Central nervous system inflammation is a process associated with several neurodegenerative disorders, including Alzheimer’s disease (AD). Many hypotheses have been postulated to explain the pathogenesis of AD. Recent findings point to amyloid-β (Aβ) oligomers as responsible for synaptic impairment in neuronal degeneration, but amyloid abnormalities are among major factors affecting the function and survival of neuronal cells. The tau protein hypothesis has been developed and refined based on the fact that tau hyperphosphorylation and self-aggregation constitutes a common feature of most of the altered signaling pathways in AD. Known mediators of inflammation have been found in plaques, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. Additional evidence for the involvement of inflammation in AD is provided by epidemiological data and retrospective clinical data showing positive effects of nonsteroidal anti-inflammatory drugs. Cytokines and trophic factors produced by glial cells can trigger anomalous hyperphosphorylation of tau. Glial production of these mediators indicates that innate immunity is involved in AD. Thus, a neuroimmunological approach to AD becomes relevant. In this context, endogenous danger signals such as altered lipoproteins and oxidized lipids appear to affect glial cells, inducing release of such mediators. Indeed, when alterations of cholesterol metabolism occur, the neurochemical events of oxidative stress, Aβ peptide, and tau protein seem to represent a set of physiological mechanisms to respond to impaired brain cholesterol dynamics. All these mechanisms, for example, changes in neuroimmunomodulation, dislipidemias, cholesterol abnormalities, and other metabolic alterations, appear to be interrelated. To date, there are no specific diagnostic tools for AD that allow early treatment, thus improving quality of life for AD patients and reducing the morbidity and mortality associated with the late complications. Therefore, a search for innovative molecular markers for early diagnosis of AD is essential. Here we discuss the molecular aspects of the role of neuroinflammation and cholesterol in AD and some perspectives toward molecular early diagnosis.