[Music] [Music] In this video we will cover the signaling events involved in the processing of amyloid precursor protein, commonly called APP, that leads to the formation of amyloid plaque. In a normal brain, an enzyme called alpha secretase acts on APP, and cleaves it into secreted APP alpha, also called sAPP alpha, and an 83 amino acid long, membrane-bound, C-terminal fragment called CTF83. Alternatively, in an Alzheimer's brain, an enzyme called beta-secretase acts on APP and cleaves it into secreted APP-beta, also called sAPP beta, and a 99 amino acid long, membrane bound, c-terminal fragment called CTF99. In normal signaling, CTF83 is further cleaved by a gamma-secretase complex made up of PSEN1, Pen-2, APH-1, GSAP, and NCT. Cleavage of CTF83 leads to the generation of APP intracellular domain otherwise known as AICD fragment. AICD fragment then translocates to the nucleus where it affects the transcriptional regulation of several proteins, and drives neuroprotective pathways. It's also important to note that sAPP alpha gets secreted from the neurons and drives normal synaptic signaling leading to synaptic plasticity, learning, memory, neuronal survival, and emotional behaviors. In Alzheimer's disease, gamma-secretase complex again is assembled, but instead cleaves the CTF99 fragment into an AICD fragment and an Abeta 40/42 peptide. AICD is again translocated to the nucleus where it affects the transcriptional regulation of several proteins and drives neuroprotective pathways. The Abeta 40/42 peptide, however, is involved in several downstream pathways related to Alzheimer's disease. Abeta 40/42 initially interacts with ApoE which results an aggregation of a beta oligomers to generate amyloid plaque. Amyloid plaque can be detected via immunohistochemistry staining using Abeta 42 specific antibodies such as clone MOAB2. Downstream, Abeta 40/42 with ApoE also interacts with mGluR5, NMDAR and alpha-7 NACHR, as well as leads to reactive oxygen species and oxidative damage. All of this results in blocked ion channels, disrupted calcium ion homeostasis, dysregulated energy glucose metabolism, mitochondrial oxidative stress, and neuronal apoptosis which ultimately results in dementia or memory loss.