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Alzheimer's Disease: Pathology and APP->AB (AMYLOID BETA PEPTIDE…
Alzheimer's Disease: Pathology and APP->AB
DISCOVERY
Cellular debris around nerves:
senile plaques
Intracellular bundles of tau protein w/in nerve cells:
neurofibrillary tangles
Extracellular plaques made of Amyloid Beta protein
BRAIN PATHOLOGY
Deposits of extracellular plaques
plaques collect in cortical interstitium (space b/w neurons) and cerebrovasculature
Amyloid plaques = Amyloid Beta peptide (AB)
Progression of AD characterized by intracellular neurofibrillary tangles
Tangles = paired helical filaments containing hyper-phosphorylated Tau protein
AMYLOID BETA PEPTIDE
39-43 residues long
Most Common: AB (1-40) & AB (1-42)
N-terminus end has acidic-charged R-groups
C-terminus end has hydrophobic R-groups
2 amino acids at C-terminus of AB-42 are variable --> make protein less soluble
AB (1-42) most neurotoxic
rapidly forms insoluble aggregates b/c more amyloidogenic form
AB (1-40) more abundant
aggregates more slowly, more soluble
Transmembrane region of AB (residues 28-42) are hydrophobic rich
AB derived from proteolysis of transmembrane glycoprotein APP (amyloid precursor protein) that's max 770 amino acids long
p3 peptide also derived from APP and found in amyloidogenic material --> contains residues 17-42 of AB peptide
APP's transmembrane domain (residues 700-723) included in Amyloid Beta peptide
Soluble AB-40 and AB-42 found in CSF and blood plasma of all humans
PRODUCING AB FROM APP
Cleaving AB from APP
(Proteolysis)
gamma
secretase (multi-protein complex w/core of presenilins PS-1 and PS-2) cuts APP w/in membrane at point along transmembrane domain ---> cutting point determines ratio of AB40 to AB42
beta
secretase cuts APP at residue 671 along extracellular domain
Secretases are potential drug inhibiting target, but research given up
gamma secretase cleavage for AB40 much
less likely
to cause Alzheimer's
Cryo-EM analysis of gamma secretase determines 3D structure (constructed w/ 2D shadows given off from various protein orientations) b/c protein impossible to crystallize b/c largely
hydrophobic and thus insoluble
Cellular Trafficking & Processing
APP goes from ER to plasma membrane via secretory pathway
~10% of APP at membrane at any given time, most in Golgi and TGN
APP endocytosed within minutes of reaching membrane
Most AB generated in cholesterol-rich membrane rafts in TGN and endosomes
In Neurons
: APP trafficked down axon, AB generated in vesicle, AB released into synaptic cleft from vesicle lumen via exocytosis & forms plaques
APP: Normal Function & Structure
Proposal
: dysfunctional APP leads to up regulation of APP, thus overproduction of AB
Approaches
: 1) Knockout mice 2) Determine structure to suggest function
Suggested Functions
: regulating synaptic development and/or cell adhesion
Entire molecular structure unknown but specific domains have been structurally determined