Claudia mori alzheimer8/11/2023 ![]() ![]() In particular, Aβ peptide and Tau aggregation inhibitors, photo-therapeutics and metal chelators are among the most promising lead but, currently, these approaches are far from being implemented in clinical practice. On the other hand, many other therapeutic approaches are under evaluation. Due to the involvement of APP metabolism in Aβ production, the inhibition of secretase enzymes represents a very promising strategy for AD treatment and clinical candidates are in phase 3 trials. Ĭurrently, the only approved therapy is focused on the limitation of symptoms by inhibiting acetylcholinesterase (AChE) action, thus enhancing cholinergic transmission. On the other hand, the intra-cellular NFT lesion results from the pathological hyperphosphorylation of protein Tau and its subsequent misfolding, aggregation and accumulation within the cytoplasm. As a consequence, an increased production of Aβ induces cell death, eventually leading to dementia. In particular, Aβ 42 is the major component in amyloid plaques and forms the most toxic oligomers. Both peptides tend to self-assemble into oligomers and then into fibrils. In turn, the cleavage of C99 by γ-secretase releases Aβ 40 and Aβ 42. ![]() The former-also known as beta-site amyloid precursor protein cleaving enzyme (BACE-1)-produces sAPP β, which is a soluble amyloid precursor and a C-terminal fragment (C99) bound to the membrane. APP is a trans-membrane protein which is cleaved by β- and γ-secretase. ![]() According to the amyloid hypothesis, Aβ peptides arise from the β-amyloid precursor protein (APP). Brains of AD patients present senile plaques formed by insoluble Aβ with a sequence between 38 and 42 amino acids. AD is mainly characterized by the anomalous processing of two proteins, amyloid-peptides (Aβ) and Tau, leading to the pathological formation of extracellular senile plaques and intracellular neurofibrillary tangles (NFTs). Among neurodegenerative diseases, Alzheimer’s (AD) represents a major concern for public health in the 21st century. ![]()
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