Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations

Chera L. Maarouf, Ian D. Daugs, Salvatore Spina, Ruben Vidal, Tyler A. Kokjohn, R. Lyle Patton, Walter M. Kalback, Dean C. Luehrs, Douglas G. Walker, Eduardo M. Castaño, Thomas G. Beach, Bernardino Ghetti, Alex E. Roher

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Abstract. Background. Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter γ-secretase activity to promote accumulation of toxic Aβ42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-β precursor protein (AβPP), Notch, N-cadherin and Erb-B4 by γ-secretase. In addition, the levels of Aβ40/42 peptides were quantified by ELISA. Results. We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Aβ40 over Aβ42. The AβPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. Conclusion. These observations imply that missense mutations in PSEN genes can alter a range of key γ-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.

Original languageEnglish
Article number20
JournalMolecular Neurodegeneration
Volume3
Issue number1
DOIs
StatePublished - 2008

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Presenilins
Dementia
Mutation
Amyloid Precursor Protein Secretases
Alzheimer Disease
Amyloid beta-Protein Precursor
Cadherins
Western Blotting
Peptides
Neurofibrillary Tangles
Densitometry
Poisons
Amyloid Plaques
Missense Mutation
Genes
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. / Maarouf, Chera L.; Daugs, Ian D.; Spina, Salvatore; Vidal, Ruben; Kokjohn, Tyler A.; Patton, R. Lyle; Kalback, Walter M.; Luehrs, Dean C.; Walker, Douglas G.; Castaño, Eduardo M.; Beach, Thomas G.; Ghetti, Bernardino; Roher, Alex E.

In: Molecular Neurodegeneration, Vol. 3, No. 1, 20, 2008.

Research output: Contribution to journalArticle

Maarouf, CL, Daugs, ID, Spina, S, Vidal, R, Kokjohn, TA, Patton, RL, Kalback, WM, Luehrs, DC, Walker, DG, Castaño, EM, Beach, TG, Ghetti, B & Roher, AE 2008, 'Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations', Molecular Neurodegeneration, vol. 3, no. 1, 20. https://doi.org/10.1186/1750-1326-3-20
Maarouf, Chera L. ; Daugs, Ian D. ; Spina, Salvatore ; Vidal, Ruben ; Kokjohn, Tyler A. ; Patton, R. Lyle ; Kalback, Walter M. ; Luehrs, Dean C. ; Walker, Douglas G. ; Castaño, Eduardo M. ; Beach, Thomas G. ; Ghetti, Bernardino ; Roher, Alex E. / Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. In: Molecular Neurodegeneration. 2008 ; Vol. 3, No. 1.
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AU - Daugs, Ian D.

AU - Spina, Salvatore

AU - Vidal, Ruben

AU - Kokjohn, Tyler A.

AU - Patton, R. Lyle

AU - Kalback, Walter M.

AU - Luehrs, Dean C.

AU - Walker, Douglas G.

AU - Castaño, Eduardo M.

AU - Beach, Thomas G.

AU - Ghetti, Bernardino

AU - Roher, Alex E.

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N2 - Abstract. Background. Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter γ-secretase activity to promote accumulation of toxic Aβ42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-β precursor protein (AβPP), Notch, N-cadherin and Erb-B4 by γ-secretase. In addition, the levels of Aβ40/42 peptides were quantified by ELISA. Results. We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Aβ40 over Aβ42. The AβPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. Conclusion. These observations imply that missense mutations in PSEN genes can alter a range of key γ-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.

AB - Abstract. Background. Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter γ-secretase activity to promote accumulation of toxic Aβ42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-β precursor protein (AβPP), Notch, N-cadherin and Erb-B4 by γ-secretase. In addition, the levels of Aβ40/42 peptides were quantified by ELISA. Results. We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Aβ40 over Aβ42. The AβPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. Conclusion. These observations imply that missense mutations in PSEN genes can alter a range of key γ-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.

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