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Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants.

Gorman PM, Kim S, Guo M, Melnyk RA, McLaurin J, Fraser PE, Bowie JU, Chakrabartty A - BMC Neurosci (2008)

Bottom Line: We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients.We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada. pgorman@westwindpartners.ca

ABSTRACT

Background: Amyloid precursor protein (APP) is enzymatically cleaved by gamma-secretase to form two peptide products, either Abeta40 or the more neurotoxic Abeta42. The Abeta42/40 ratio is increased in many cases of familial Alzheimer's disease (FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains.

Results: Using synthetic peptides derived from the APP-TM domain, we show that this segment is capable of forming stable transmembrane dimers. A model of a dimeric APP-TM domain reveals a putative dimerization interface, and interestingly, majority of FAD mutations in APP are localized to this interface region. We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.

Conclusion: The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.

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Related in: MedlinePlus

Comparison to the clinical pathology of AD patients. The dimerization constants of the APP-TM peptides were compared to the A) Aβ42/Aβ40 ratio and B) mean age of onset. The mean age of onset was obtained from all available families [2]. The dissociation constants are positively correlated to the Aβ42/Aβ40 ratios and similarly association constants are equally correlated to the mean age of onset.
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Figure 6: Comparison to the clinical pathology of AD patients. The dimerization constants of the APP-TM peptides were compared to the A) Aβ42/Aβ40 ratio and B) mean age of onset. The mean age of onset was obtained from all available families [2]. The dissociation constants are positively correlated to the Aβ42/Aβ40 ratios and similarly association constants are equally correlated to the mean age of onset.

Mentions: The dissociation constants of the APP-TM variants were compared to the Aβ42/Aβ40 ratio and the mean age of onset for the different mutations (Fig. 6). Mean age of onset for the different mutations was calculated using all available families [2]. Aβ42/Aβ40 ratios were obtained from published studies using familial Alzheimer's disease brain or cell cultures [10-12]. The dissociation constants exhibited a direct correlation to the critical Aβ42/Aβ40 ratio (R = 0.993); the mutation-induced increases in the dissociation constants were mirrored by increases in the Aβ42/Aβ40 ratio in these FAD cases. Strikingly, the APP-TM association constant were also directly correlated to the mean age of onset of AD (R = 0.993), that is, the weaker the association constant, the earlier the age of onset of AD symptoms.


Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants.

Gorman PM, Kim S, Guo M, Melnyk RA, McLaurin J, Fraser PE, Bowie JU, Chakrabartty A - BMC Neurosci (2008)

Comparison to the clinical pathology of AD patients. The dimerization constants of the APP-TM peptides were compared to the A) Aβ42/Aβ40 ratio and B) mean age of onset. The mean age of onset was obtained from all available families [2]. The dissociation constants are positively correlated to the Aβ42/Aβ40 ratios and similarly association constants are equally correlated to the mean age of onset.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2266763&req=5

Figure 6: Comparison to the clinical pathology of AD patients. The dimerization constants of the APP-TM peptides were compared to the A) Aβ42/Aβ40 ratio and B) mean age of onset. The mean age of onset was obtained from all available families [2]. The dissociation constants are positively correlated to the Aβ42/Aβ40 ratios and similarly association constants are equally correlated to the mean age of onset.
Mentions: The dissociation constants of the APP-TM variants were compared to the Aβ42/Aβ40 ratio and the mean age of onset for the different mutations (Fig. 6). Mean age of onset for the different mutations was calculated using all available families [2]. Aβ42/Aβ40 ratios were obtained from published studies using familial Alzheimer's disease brain or cell cultures [10-12]. The dissociation constants exhibited a direct correlation to the critical Aβ42/Aβ40 ratio (R = 0.993); the mutation-induced increases in the dissociation constants were mirrored by increases in the Aβ42/Aβ40 ratio in these FAD cases. Strikingly, the APP-TM association constant were also directly correlated to the mean age of onset of AD (R = 0.993), that is, the weaker the association constant, the earlier the age of onset of AD symptoms.

Bottom Line: We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients.We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada. pgorman@westwindpartners.ca

ABSTRACT

Background: Amyloid precursor protein (APP) is enzymatically cleaved by gamma-secretase to form two peptide products, either Abeta40 or the more neurotoxic Abeta42. The Abeta42/40 ratio is increased in many cases of familial Alzheimer's disease (FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains.

Results: Using synthetic peptides derived from the APP-TM domain, we show that this segment is capable of forming stable transmembrane dimers. A model of a dimeric APP-TM domain reveals a putative dimerization interface, and interestingly, majority of FAD mutations in APP are localized to this interface region. We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.

Conclusion: The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.

Show MeSH
Related in: MedlinePlus