[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.
