Alzheimer’s Disease Signaling
Figure.1 Molecular and Cellular Biology of Alzheimer’s Disease
Alzheimer's disease is one of the most common neurodegenerative diseases in the world. The clinical manifestations are extracellular amyloid plaques and intracellular neurofibrillary tangles that lead to neuronal dysfunction and cell death. At the heart of the disease is differential processing of the amyloid precursor protein (APP). APP is a complete membrane protein treated with proteolysis. APP is initially cleaved by α-secretory enzymes to form sAPPα and C83 carboxy-terminal fragments. The presence of sAPP alpha is associated with normal synaptic signaling and regulates processes such as neuronal survival and synaptic plasticity, which contribute to higher order brain functions such as learning and memory, among other behaviors. APP can also be cleaved sequentially by β-secretase and γ-secretase to release extracellular monomers of different sizes, the most important of which is Aβ40/42. In the disease state, the imbalance between APP treatment pathways leads to increased aggregation of neurotoxic monomers, Aβ oligomerization and plaque formation. The accumulation of pathogenic Aβ leads to ion channel obstruction, disruption of calcium homeostasis, mitochondrial oxidative stress, impaired energy metabolism and abnormal glucose regulation, altered synaptic function, and ultimately neuronal cell death. Some glial cell types, including astrocytes and microglia, are thought to be neuroprotective and pathogenic in the context of amyloid, oligomers, and plaque buildup. Another characteristic of Alzheimer's disease is the presence of neurofibrillary tangles, which consist of hyperphosphorylated forms of the microtubule-associated protein Tau. GSK-3α/β and CDK5 are the kinases primarily responsible for Tau phosphorylation, although other kinases such as PKC, PKA and Erk2 are also involved. Hyperphosphorylation of Tau leads to Tau separation from microtubules, followed by microtubule instability and Tau oligomerization, eventually leading to intracellular neurofibrillary tangles. The gradual accumulation of these tangles leads to neuronal apoptosis.
Although Alzheimer's disease poses a significant threat to human nervous system health, only a few drugs have been approved for the treatment of the disease. And the drugs often work only to control symptoms, hardly altering the course of the disease. Through the study and summary of a large number of cases and clinical results, researchers have also proposed a variety of different theories to explain the pathogenesis of Alzheimer's disease, among which the widely accepted and carried out drug design and research are mainly as follows: Amyloid cascade hypothesis, Tau hypothesis and Cholinergic hypothesis, etc. Aladdin can provide you with hundreds of active compounds for research and treatment of Alzheimer's disease.
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