Abstract
Alzheimer’s disease (AD) is recognized as a major health hazard that mostly affects people older than 60 years. AD is one of the biggest medical, economic, and social concerns to patients and their caregivers. AD was ranked as the 5th leading cause of global deaths in 2016 by the World Health Organization (WHO). Many drugs targeting the production, aggregation, and clearance of Aβ plaques failed to give any conclusive clinical outcomes. This mainly stems from the fact that AD is not a disease attributed to a single-gene mutation. Two hallmarks of AD, Aβ plaques and neurofibrillary tangles (NFTs), can simultaneously induce other AD etiologies where every pathway is a loop of consequential events. Therefore, the focus of recent AD research has shifted to exploring other etiologies, such as neuroinflammation and central hyperexcitability. Neuroinflammation results from the hyperactivation of microglia and astrocytes that release pro-inflammatory cytokines due to the neurological insults caused by Aβ plaques and NFTs, eventually leading to synaptic dysfunction and neuronal death. This review will report the failures and side effects of many anti-Aβ drugs. In addition, emerging treatments targeting neuroinflammation in AD, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and receptor-interacting serine/threonine protein kinase 1 (RIPK1), that restore calcium dyshomeostasis and microglia physiological function in clearing Aβ plaques, respectively, will be deliberately discussed. Other novel pharmacotherapy strategies in treating AD, including disease-modifying agents (DMTs), repurposing of medications used to treat non-AD illnesses, and multi target-directed ligands (MTDLs) are also reviewed. These approaches open new doors to the development of AD therapy, especially combination therapy that can cater for several targets simultaneously, hence effectively slowing or stopping AD.
Highlights
Alzheimer's disease (AD) is a chronic neurodegenerative disease that usually affects people older than 60 years
Various mechanisms were associated with the sporadic form of AD, which accounts for most AD cases, whereas mutations of three genes, including amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) are heavily linked with familial AD cases (Newman et al, 2017)
We are still encountering a lack of success in pharmacotherapy of AD, mostly due to the multifactorial etiologies of the disorder that can initiate neurodegeneration interdependently
Summary
Alzheimer's disease (AD) is a chronic neurodegenerative disease that usually affects people older than 60 years. The etiologies of many neurodegenerative diseases are not limited to a single gene or pathway, but are rather an intricate network of causatives, including neuroinflammation, oxidative stress, mitochondrial dysfunction, protein misfolding, and aggregation that can lead to cell death (Wu et al, 2018; Kamil et al, 2019). Ab plaques trigger the activation of microglia and astrocyte as an inflammatory response, alter the neuronal calcium homeostasis causing oxidative injury, and disrupt the protein kinase and phosphatase-related pathways, resulting in hyperphosphorylation of tau and formation of NFTs (Reiman, 2016). Self-propagation of Ab42 plaques and hyperphosphorylated tau, via a prion-like mechanism, may exaggerate the synaptic dysfunction, neurotransmitter deficits, and neuronal loss in the brain (Goedert, 2015). Hyperphosphorylation of tau sequesters the normal tau in which it may excessively impair tau binding and destabilize MTs, impairing the axonal transport causing neurodegeneration
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