Amyloid Cascade Hypothesis

Amyloid Cascade Hypothesis

The amyloid cascade hypothesis is the most widely accepted of the AD pathogenesis hypotheses. Its principle is that the accumulation of Aβ plays a major role in AD pathogenesis, and the disease is analyzed as a series of abnormalities in the process and secretion of the amyloid precursor protein (APP), where an inequality between production and clearance of amyloid β is the triggering event and the most important factor responsible for other abnormalities observed in AD (Hardy et al, 2002; Cummings et al, 2007). Amyloid β is a peptide with high resistance to proteolytic degradation. It consists of 37–43 amino acids with different isoforms (Deane et al, 2009). Aβ is the result of sequential cleavage of the amyloid precursor protein (APP), generating ... Show more content on Helpwriting.net ...Autosomal dominant mutations in APP, PSEN1, or PSEN2 that alter APP processing and the production or self aggregation of Aβ, promote aggregation and accumulation of Aβ in brain causing early–onset AD (Bertram et al., 2010).

It has been found that the oligomeric forms of Aβ were more dangerous than its monomers, acting intracellularly and extracellularly leading to the disruption of several downstream mechanisms, such as the disruption of intracellular calcium homeostasis (Camandola and Mattson, 2011), and impairments of axonal transport and mitochondrial functions (Decker et al., 2010; Querfurth and LaFerla, 2010; Sheng and Cai, 2012). In addition, several lines of evidence suggest that Aβ regulates neuronal and synaptic activities and that its accumulation in the brain causes aberrant network activity and synaptic depression (Palop and Mucke, 2010). Impairments of inhibitory interneurons and aberrant stimulation of glutamate receptors result in excitotoxicity, and play important upstream roles in this pathogenic cascade. These impairments also lead to a positive feedback loop, where aberrant neuronal activity augments Aβ production, which in turn leads to further neuronal damage (Palop and Mucke, 2010; Bero et al., 2011; Verret et al.,

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