Induced dimerization of the amyloid precursor protein leads to decreased amyloid-beta protein production

Topic: Brain proteins, microglia and lab models

The amyloid precursor protein (APP) plays a central role in Alzheimer disease (AD) pathogenesis because sequential cleavages by beta- and gamma-secretase lead to the generation of the amyloid-beta (Abeta) peptide, a key constituent in the amyloid plaques present in brains of AD individuals. In several studies APP has recently been shown to form homodimers, and this event appears to influence Abeta generation. However, these studies have relied on APP mutations within the Abeta sequence itself that may affect APP processing by interfering with secretase cleavages independent of dimerization.

@article{eggert2009-19596858,
  author  = {Eggert, S. and Midthune, B. and Cottrell, B. and Koo, E. H.},
  title   = {{Induced dimerization of the amyloid precursor protein leads to decreased amyloid-beta protein production}},
  journal = {The Journal of biological chemistry},
  year    = {2009},
  doi     = {10.1074/jbc.m109.038646},
  pmid    = {19596858},
  url     = {https://doi.org/10.1074/jbc.m109.038646}
}

Key findings

• In several studies APP has recently been shown to form homodimers, and this event appears to influence Abeta generation.
• However, these studies have relied on APP mutations within the Abeta sequence itself that may affect APP processing by interfering with secretase cleavages independent of dimerization.
• Therefore, the impact of APP dimerization on Abeta production remains unclear.
• To address this question, we compared the approach of constitutive cysteine-induced APP dimerization with a regulatable dimerization system that does not require the introduction of mutations within the Abeta sequence.

Why it matters

Forcing the amyloid precursor protein to form dimers decreased amyloid-beta production in this laboratory study. This points to amyloid precursor protein dimerization as a possible way to lower amyloid-beta, but it is early cell-based work and not a treatment.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1074/jbc.m109.038646
• PubMed: 19596858
• Original source →
• Free full text: Journal of Biological Chemistry →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• β-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE Science · 1999-10-22 · usefulness score 64/100 · Disease mechanisms
• The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor Nature · 1987-02-01 · usefulness score 58/100 · Disease mechanisms
• Amyloid plaque core protein in Alzheimer disease and Down syndrome Proceedings of the National Academy of Sciences of the United States of America · 1985-06-01 · usefulness score 56/100 · Down syndrome and Alzheimer's
• Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein Biochemical and Biophysical Research Communications · 1984-05-01 · usefulness score 54/100 · Disease mechanisms
• A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing Biochemistry · 2002-02-01 · usefulness score 45/100 · Risk genes beyond APOE
• Amyloidogenic processing but not amyloid precursor protein (APP) intracellular C-terminal domain production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs The Journal of biological chemistry · 2008-01-16 · usefulness score 44/100 · Risk genes beyond APOE

Related studies in Risk genes beyond APOE

• beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity Cell · 1995-05-01 · usefulness score 36/100
• Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production Cell death and differentiation · 2009-01-16 · usefulness score 46/100
• Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells The Journal of biological chemistry · 1995-03-01 · usefulness score 45/100
• The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production The Journal of biological chemistry · 2005-06-27 · usefulness score 45/100
• Copper inhibits beta-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion The Biochemical journal · 1999-12-01 · usefulness score 41/100
• BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production The Journal of biological chemistry · 2005-07-18 · usefulness score 41/100

Also tagged “precursor”

1,339 studies in the library carry the topic tag “precursor”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.

• Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Abeta peptide Biochemistry · 2001-12-01 · usefulness score 44/100 · Genetics
• The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations The Lancet. Neurology · 2011-03-01 · usefulness score 49/100 · Caregiving
• Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci Annals of neurology · 2015-07-28 · usefulness score 58/100 · Genetics

Similar studies

• Amyloid-β production via cleavage of amyloid-β protein precursor is modulated by cell density 2010 · Biomarkers
• Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory 2008 · Disease mechanisms
• Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production 1992 · Risk genes beyond APOE
• Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the γ-secretase cleavage sites 2017 · Biomarkers
• Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors 1995 · Risk genes beyond APOE
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More on Risk genes beyond APOE

• A review that covers this ground Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments Neurology · 2006-01-01 · usefulness score 47/100
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