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The progress in understanding the pathogenesis and treatment of Alzheimer’s disease (AD) is based on the recognition of the primary causes of the disease, which can be deduced from the knowledge of risk factors and biomarkers measurable in the early stages of the disease. Insights into the risk factors and the time course of biomarker abnormalities point to a role for the connection of amyloid beta (Aβ) pathology, tau pathology, mitochondrial dysfunction, and oxidative stress in the onset and development of AD. Coenzyme Q10 (CoQ10) is a lipid antioxidant and electron transporter in the mitochondrial electron transport system. The availability and activity of CoQ10 is crucial for proper mitochondrial function and cellular bioenergetics. Based on the mitochondrial hypothesis of AD and the hypothesis of oxidative stress, the regulation of the efficiency of the oxidative phosphorylation system by means of CoQ10 can be considered promising in restoring the mitochondrial function impaired in AD, or in preventing the onset of mitochondrial dysfunction and the development of amyloid and tau pathology in AD. This review summarizes the knowledge on the pathophysiology of AD, in which CoQ10 may play a significant role, with the aim of evaluating the perspective of the pharmacotherapy of AD with CoQ10 and its analogues.

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer’s disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

Several neurodegenerative disorders including Alzheimer’s disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease’s progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.