A-beta Pathways: Plaque Formation & APP Metabolism

Click on one of the boxes below to view the molecular mechanisms involved in this stage of APP processing, A-beta secretion, and plaque formation.

A-beta Oligomers
A-beta Oligomers
ACE
ACE
Insulysin/IDE
Insulysin/IDE
MMP-2
MMP-2
MMP-9
MMP-9
Neprilysin
Neprilysin

Plaque Formation

Plaque Formation

Oligomerization

Oligomerization

A-beta Oligomers
A-beta Oligomers
A-beta Plaque
A-beta Plaque

Plaque Formation

Plaque Formation

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Plasminogen
Plasminogen
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tPA/uPA
tPA/uPA
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Plasmin
Plasmin
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Cystatin C
Cystatin C
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Cathepsin B
Cathepsin B

Secretion of
A-beta monomers

Secretion of
A-beta monomers

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sAPP alpha
sAPP alpha
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alpha-CTF
alpha-CTF
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alpha-
Secretase
alpha-
Secretase
APP
APP
gamma-
Secretase
gamma-
Secretase
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alpha-CTF
alpha-CTF
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Neuron
Neuron
Endosome
Endosome
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AICD
AICD
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p3
p3
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APP
APP
Trans-Golgi Network
Trans-Golgi Network
APP
APP
beta-
Secretase
beta-
Secretase
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beta-CTF
beta-CTF
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sAPP beta
sAPP beta
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AICD
AICD
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gamma-
Secretase
gamma-
Secretase
A-beta
A-beta
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beta-CTF
beta-CTF
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Overview of APP Metabolism & A-beta Plaque Formation

Sporadic, or late-onset, AD affects approximately 10% of the population over the age of sixty-five, making it the most prevalent neurodegenerative disorder. This devastating condition is characterized by progressive cognitive impairment and neurodegeneration, commencing in the hippocampus and cortex. Neuropathological hallmarks of AD include neuronal loss in the presence of neurofibrillary tangles and senile plaques. Neurofibrillary tangles are intraneuronal inclusions composed of insoluble hyperphosphorylated forms of the microtubule protein Tau. Senile plaques represent extracellular deposits of aggregated Amyloid-beta protein (A-beta), the proposed causative agent of AD. Prior to its deposition as senile plaques, A-beta oligomerizes to exert pathological actions on neuron function and viability.

A-beta is generated by sequential enzymatic processing of Amyloid Precursor Protein (APP), a type I transmembrane protein. The majority of APP is cleaved by alpha-Secretase, which does not produce A-beta and is termed non-amyloidogenic. Putative alpha-Secretases include ADAM9, ADAM10, and TACE/ADAM17. In contrast, a small percentage of APP is processed by beta-Secretases, such as BACE-1 and Cathepsin D, which yields soluble APP-beta (sAPP-beta) and a beta-C-terminal Fragment (beta-CTF). The beta-CTF fragment is further cleaved by gamma-Secretase to generate A-beta. The activity of gamma-Secretase requires four components; Presenilin-1 (PS-1) or PS-2, Presenilin Enhancer-2 (PEN-2), Nicastrin, and Anterior Pharynxdefective-1 (Aph-1). Mutations in APP and PS, which increase amyloidogenic processing of APP, cause the majority of early-onset familial Alzheimer’s disease (FAD).

To learn more, please visit our APP Cleavage and Amyloid-beta Degradation Research Area.

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