Alzheimer's Disease, Oligomers, and Inflammation

Abstract

The production of soluble amyloid-β oligomers (AβOs) and the activation of inflammation are two important early steps in the pathogenesis of Alzheimer's disease (AD). The central role of oligomers as responsible for the neuronal dysfunction associated with the clinical features has been extended to the other protein misfolding disorders definable, on this basis, as oligomeropathies. In AD, recent evidence indicates that the mechanism of inflammation as a consequence of neurodegeneration must be assessed in favor of a more direct role of glial activation in the alteration of synaptic function. Our own experimental models demonstrate the efficacy of anti-inflammatory treatments in preventing the cognitive deficits induced acutely by AβOs applied directly in the brain. Moreover, some promising clinical tools are based on immunological activation reducing the presence of cerebral Aβ deposits. However, the strategies based on the control of inflammatory factors as well as the amyloid aggregation show poor or non-therapeutic efficacy. Numerous studies have examined inflammatory factors in biological fluids as possible markers of the neuroinflammation in AD. In some cases, altered levels of cytokines or other inflammatory markers in cerebrospinal fluid correlate with the severity of the disease. Here we propose, according to the precision medicine principles, innovative therapeutic approaches to AD based on the patient's inflammatory profile/state. The earlier intervention and a multifactor approach are two other elements considered essential to improve the chances of effective therapy in AD.

Keywords: Alzheimer’s disease therapy; amyloid; anti-inflammatory drugs; glial cells; immune system; oligomeropathy; precision medicine; toll-like receptors.

Fig.1

The cartoon illustrates several aspects of AD pathogenesis starting from the formation of Aβ oligomers, a variety of entities with different sizes, peptide combinations and conformations (in light blue and blue); the seeding passage with conformation change (from square to circle) may also occur intracellularly. The oligomers in dynamic equilibrium with senile plaques can act directly at the neuronal level or induce neuronal dysfunction through glial activation by the production of cytokines radicals and other factors. In our experimental studies [133], we found that anti-inflammatory drugs, doxycyline and a TLR-4 antagonist antagonized the cognitive decline induced by direct intracerebral injection of Aβ oligomers.