Alzheimer’s disease beyond the amyloid accumulation

Abstract Alzheimer’s disease represents one of the unsolved problems of modern medicine, which assumes a significant financial burden in the research, medical, and social fields as well. Treatments intended for preventing and slowing neurodegenerative processes are the subject of a considerable amount of research and clinical trials, but the results are still insignificant regarding the clinical applicability. Initially, we believed that slow neurodegeneration can be traced back entirely to the accumulation of β-amyloid proteins with atypical structure and behavior in certain areas of the brain. This theory was constantly supplemented by the observation of intracellularly aggregating neurofibrillary tangles and the formulation of neuroinflammatory mechanisms. In this regard Alzheimer’s disease-associated neuroinflammation is an immunological response to the presence of β-amyloid oligomers, which initially leads to microglial activation and inflammatory cytokine release. Over time, this process becomes chronic, extending to astrocytes, neurons, and brain microvascularization, and leading to functional impairment, which is clinically manifested in cognitive and memory deficits. The defined central role of neuroinflammation was overturned by the therapeutic failure of drugs with anti-inflammatory capacity. Subsequently, our knowledge was completed by the recognition of how oxidative stress and the altered brain insulin signaling influences metabolic processes, opening new perspectives for drug development. Despite this, new drug candidates are successively failing, as complex regulatory mechanisms have been identified that question the initial triggering role of the β-amyloid and the final impairing effect of the inflammation. The aim of this study is to summarize and present the biochemical and pathophysiological knowledge that contributed to the currently available more comprehensive picture and a more detailed understanding of the processes of Alzheimer’s disease. Properly planned and executed preclinical experiments are essential to establish further clinical conclusions. By the comparison of the currently used rodent models, we tried to draw attention to the complexity of animal experiments and the importance of their multi-level (behavioral, biochemical, histological) evaluation.