Presenilin-1 280Glu→ala mutation alters C-terminal APP processing yielding longer Aβ peptides: Implications for Alzheimer's disease

Gregory D. Van Vickle, Chera L. Esh, Tyler A. Kokjohn, R. Lyle Patton, Walter M. Kalback, Dean C. Luehrs, Thomas G. Beach, Amanda J. Newel, Francisco Lopera, Bernardino Ghetti, Ruben Vidal, Eduardo M. Castaño, Alex E. Roher

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Presenilin (PS) mutations enhance the production of the Aβ42 peptide that is derived from the amyloid precursor protein (APP). The pathway(s) by which the Aβ42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established. Using a combination of histological, immunohistochemical, biochemical, and mass spectrometric methods, we examined the structural and morphological nature of the amyloid species produced in a patient expressing the PS1 280Glu→Ala familial Alzheimer's disease mutation. Abundant diffuse plaques were observed that exhibited a staining pattern and morphology distinct from previously described PS cases, as well as discreet amyloid plaques within the white matter. In addition to finding increased amounts of CT99 and Aβ42 peptides, our investigation revealed the presence of a complex array of Aβ peptides substantially longer than 42/43 amino acid residue species. The increased hydrophobic nature of longer Aβ species retained within the membrane walls could impact the structure and function of plasma membrane and organelles. These C-terminally longer peptides may, through steric effects, dampen the rate of turnover by critical amyloid degrading enzymes such as neprilysin and insulin degrading enzyme. A complete understanding of the deleterious side effects of membrane bound Aβ as a consequence of γ-secretase alterations is needed to understand Alzheimer's disease pathophysiology and will aid in the design of therapeutic interventions.

Original languageEnglish
Pages (from-to)184-194
Number of pages11
JournalMolecular Medicine
Volume14
Issue number3-4
DOIs
StatePublished - Mar 2008

Fingerprint

Presenilins
Presenilin-1
Amyloid beta-Protein Precursor
Alzheimer Disease
Amyloid
Peptides
Mutation
Insulysin
Neprilysin
Amyloid Precursor Protein Secretases
Membranes
Amyloid Plaques
Organelles
Dementia
Cell Membrane
Staining and Labeling
Amino Acids
Enzymes
peptide A42
Therapeutics

ASJC Scopus subject areas

  • Genetics

Cite this

Van Vickle, G. D., Esh, C. L., Kokjohn, T. A., Patton, R. L., Kalback, W. M., Luehrs, D. C., ... Roher, A. E. (2008). Presenilin-1 280Glu→ala mutation alters C-terminal APP processing yielding longer Aβ peptides: Implications for Alzheimer's disease. Molecular Medicine, 14(3-4), 184-194. https://doi.org/10.2119/2007-00094.Van Vickle

Presenilin-1 280Glu→ala mutation alters C-terminal APP processing yielding longer Aβ peptides : Implications for Alzheimer's disease. / Van Vickle, Gregory D.; Esh, Chera L.; Kokjohn, Tyler A.; Patton, R. Lyle; Kalback, Walter M.; Luehrs, Dean C.; Beach, Thomas G.; Newel, Amanda J.; Lopera, Francisco; Ghetti, Bernardino; Vidal, Ruben; Castaño, Eduardo M.; Roher, Alex E.

In: Molecular Medicine, Vol. 14, No. 3-4, 03.2008, p. 184-194.

Research output: Contribution to journalArticle

Van Vickle, GD, Esh, CL, Kokjohn, TA, Patton, RL, Kalback, WM, Luehrs, DC, Beach, TG, Newel, AJ, Lopera, F, Ghetti, B, Vidal, R, Castaño, EM & Roher, AE 2008, 'Presenilin-1 280Glu→ala mutation alters C-terminal APP processing yielding longer Aβ peptides: Implications for Alzheimer's disease', Molecular Medicine, vol. 14, no. 3-4, pp. 184-194. https://doi.org/10.2119/2007-00094.Van Vickle
Van Vickle, Gregory D. ; Esh, Chera L. ; Kokjohn, Tyler A. ; Patton, R. Lyle ; Kalback, Walter M. ; Luehrs, Dean C. ; Beach, Thomas G. ; Newel, Amanda J. ; Lopera, Francisco ; Ghetti, Bernardino ; Vidal, Ruben ; Castaño, Eduardo M. ; Roher, Alex E. / Presenilin-1 280Glu→ala mutation alters C-terminal APP processing yielding longer Aβ peptides : Implications for Alzheimer's disease. In: Molecular Medicine. 2008 ; Vol. 14, No. 3-4. pp. 184-194.
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