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

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 - Mol Neurodegener (2008)

Bottom Line: 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-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase.There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City, AZ 85351, USA. alex.roher@bannerhealth.com.

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 gamma-secretase activity to promote accumulation of toxic Abeta42 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-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 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 Abeta40 over Abeta42. The AbetaPP 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 gamma-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.

No MeSH data available.


Related in: MedlinePlus

Western blots of the 80 kDa Notch-1 intracellular domain (NICD) and N-cadherin/CTF2.A) Notice that, with the exception of 3 PSEN mutation cases (Y115C/PSEN1, N141I/PSEN2 and P264L/PSEN1), all the PSEN mutations have reduced quantities of NICD transcription factor. In the SAD cases, there is a heterogeneous distribution of NICD, being almost negligible in one SAD case, elevated in a second case and diminished in the remaining two, relative to the ND controls. B) The amount of N-Cadherin holoprotein detected at 110 kDa is reduced in all PSEN cases relative to the ND controls. A similar pattern is observed for the SAD cases. The N-Cad/CTF2 band at 28 kDa is decreased in all PSEN mutations with the exception of A260V and M146L mutations that displayed higher values. The quantities of the N-Cad/CTF2 were variable in the SAD relative to the ND levels. SAD = sporadic Alzheimer's disease; ND = non-demented.
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Figure 6: Western blots of the 80 kDa Notch-1 intracellular domain (NICD) and N-cadherin/CTF2.A) Notice that, with the exception of 3 PSEN mutation cases (Y115C/PSEN1, N141I/PSEN2 and P264L/PSEN1), all the PSEN mutations have reduced quantities of NICD transcription factor. In the SAD cases, there is a heterogeneous distribution of NICD, being almost negligible in one SAD case, elevated in a second case and diminished in the remaining two, relative to the ND controls. B) The amount of N-Cadherin holoprotein detected at 110 kDa is reduced in all PSEN cases relative to the ND controls. A similar pattern is observed for the SAD cases. The N-Cad/CTF2 band at 28 kDa is decreased in all PSEN mutations with the exception of A260V and M146L mutations that displayed higher values. The quantities of the N-Cad/CTF2 were variable in the SAD relative to the ND levels. SAD = sporadic Alzheimer's disease; ND = non-demented.

Mentions: Analysis of Notch-1 by WB suggested that the S3 cleavage was negligible in seven of the ten PSEN mutations, since the levels of the ~80 kDa NICD were very low. However, we cannot exclude the possibility of a faster turnover of the fragment resulting in lower steady-state levels. Two of the remaining three cases (P264L and N141I), exhibited lesser amounts of the 80 kDa NICD when compared to ND controls, while the remaining case (Y115C) had comparable values to ND controls (Figure 6A). The detected amounts of the NICD peptide in SAD were very heterogeneous. In one case only trace amounts of NICD were present. In two cases this peptide existed at lower levels than those in ND controls while in one individual the level was higher than the ND controls (Figure 6A).


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

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 - Mol Neurodegener (2008)

Western blots of the 80 kDa Notch-1 intracellular domain (NICD) and N-cadherin/CTF2.A) Notice that, with the exception of 3 PSEN mutation cases (Y115C/PSEN1, N141I/PSEN2 and P264L/PSEN1), all the PSEN mutations have reduced quantities of NICD transcription factor. In the SAD cases, there is a heterogeneous distribution of NICD, being almost negligible in one SAD case, elevated in a second case and diminished in the remaining two, relative to the ND controls. B) The amount of N-Cadherin holoprotein detected at 110 kDa is reduced in all PSEN cases relative to the ND controls. A similar pattern is observed for the SAD cases. The N-Cad/CTF2 band at 28 kDa is decreased in all PSEN mutations with the exception of A260V and M146L mutations that displayed higher values. The quantities of the N-Cad/CTF2 were variable in the SAD relative to the ND levels. SAD = sporadic Alzheimer's disease; ND = non-demented.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2600784&req=5

Figure 6: Western blots of the 80 kDa Notch-1 intracellular domain (NICD) and N-cadherin/CTF2.A) Notice that, with the exception of 3 PSEN mutation cases (Y115C/PSEN1, N141I/PSEN2 and P264L/PSEN1), all the PSEN mutations have reduced quantities of NICD transcription factor. In the SAD cases, there is a heterogeneous distribution of NICD, being almost negligible in one SAD case, elevated in a second case and diminished in the remaining two, relative to the ND controls. B) The amount of N-Cadherin holoprotein detected at 110 kDa is reduced in all PSEN cases relative to the ND controls. A similar pattern is observed for the SAD cases. The N-Cad/CTF2 band at 28 kDa is decreased in all PSEN mutations with the exception of A260V and M146L mutations that displayed higher values. The quantities of the N-Cad/CTF2 were variable in the SAD relative to the ND levels. SAD = sporadic Alzheimer's disease; ND = non-demented.
Mentions: Analysis of Notch-1 by WB suggested that the S3 cleavage was negligible in seven of the ten PSEN mutations, since the levels of the ~80 kDa NICD were very low. However, we cannot exclude the possibility of a faster turnover of the fragment resulting in lower steady-state levels. Two of the remaining three cases (P264L and N141I), exhibited lesser amounts of the 80 kDa NICD when compared to ND controls, while the remaining case (Y115C) had comparable values to ND controls (Figure 6A). The detected amounts of the NICD peptide in SAD were very heterogeneous. In one case only trace amounts of NICD were present. In two cases this peptide existed at lower levels than those in ND controls while in one individual the level was higher than the ND controls (Figure 6A).

Bottom Line: 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-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase.There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City, AZ 85351, USA. alex.roher@bannerhealth.com.

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 gamma-secretase activity to promote accumulation of toxic Abeta42 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-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 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 Abeta40 over Abeta42. The AbetaPP 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 gamma-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.

No MeSH data available.


Related in: MedlinePlus