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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 Erb-B4. Overall, the bands corresponding to the holoprotein (~180 kDa) and ~60 kDa were decreased in all PSEN mutations as well as in the SAD cases relative to the ND controls. Of the degradation peptides that carry the Erb-B4 C-terminal epitope the most represented band, at ~55 kDa, demonstrated heterogeneous levels among different PSEN mutations. In the SAD cases the values were more similar to the control levels. The ~50 and ~30 kDa peptide bands also show large deviations among the PSEN, SAD and ND controls. The ~40 kDa band was increased in the ND controls when compared to the PSEN and SAD cases. SAD = sporadic Alzheimer's disease; ND = non-demented.
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Figure 7: Western blots of Erb-B4. Overall, the bands corresponding to the holoprotein (~180 kDa) and ~60 kDa were decreased in all PSEN mutations as well as in the SAD cases relative to the ND controls. Of the degradation peptides that carry the Erb-B4 C-terminal epitope the most represented band, at ~55 kDa, demonstrated heterogeneous levels among different PSEN mutations. In the SAD cases the values were more similar to the control levels. The ~50 and ~30 kDa peptide bands also show large deviations among the PSEN, SAD and ND controls. The ~40 kDa band was increased in the ND controls when compared to the PSEN and SAD cases. SAD = sporadic Alzheimer's disease; ND = non-demented.

Mentions: The total levels of Erb-B4 (~180 kDa) were reduced in the PSEN mutations, relative to ND cases as revealed by WB. A similar pattern was observed in the SAD cohort (Figure 7). In PSEN and SAD individuals there was a reduction of the ~60 kDa peptide. The most prominent band (~55 kDa) showed variable quantities among the PSEN mutations and ND controls. Cases F105L and P264L had the highest amounts of the ~50 kDa band with the remaining PSEN cases and ND controls having similar quantities. In most of the PSEN mutations the ~40 kDa band was 2–10 fold diminished, while the ~30 kDa peptide had heterogeneous values (Figure 7). Absorption experiments by ourselves (data not shown) and others [65,66], revealed that the fragments were specific to Erb-B4. Overall, the WB patterns suggest that in the PSEN mutations, Erb-B4 has a high degree of variation in CT peptide degradation (Figure 7).


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 Erb-B4. Overall, the bands corresponding to the holoprotein (~180 kDa) and ~60 kDa were decreased in all PSEN mutations as well as in the SAD cases relative to the ND controls. Of the degradation peptides that carry the Erb-B4 C-terminal epitope the most represented band, at ~55 kDa, demonstrated heterogeneous levels among different PSEN mutations. In the SAD cases the values were more similar to the control levels. The ~50 and ~30 kDa peptide bands also show large deviations among the PSEN, SAD and ND controls. The ~40 kDa band was increased in the ND controls when compared to the PSEN and SAD cases. SAD = sporadic Alzheimer's disease; ND = non-demented.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2600784&req=5

Figure 7: Western blots of Erb-B4. Overall, the bands corresponding to the holoprotein (~180 kDa) and ~60 kDa were decreased in all PSEN mutations as well as in the SAD cases relative to the ND controls. Of the degradation peptides that carry the Erb-B4 C-terminal epitope the most represented band, at ~55 kDa, demonstrated heterogeneous levels among different PSEN mutations. In the SAD cases the values were more similar to the control levels. The ~50 and ~30 kDa peptide bands also show large deviations among the PSEN, SAD and ND controls. The ~40 kDa band was increased in the ND controls when compared to the PSEN and SAD cases. SAD = sporadic Alzheimer's disease; ND = non-demented.
Mentions: The total levels of Erb-B4 (~180 kDa) were reduced in the PSEN mutations, relative to ND cases as revealed by WB. A similar pattern was observed in the SAD cohort (Figure 7). In PSEN and SAD individuals there was a reduction of the ~60 kDa peptide. The most prominent band (~55 kDa) showed variable quantities among the PSEN mutations and ND controls. Cases F105L and P264L had the highest amounts of the ~50 kDa band with the remaining PSEN cases and ND controls having similar quantities. In most of the PSEN mutations the ~40 kDa band was 2–10 fold diminished, while the ~30 kDa peptide had heterogeneous values (Figure 7). Absorption experiments by ourselves (data not shown) and others [65,66], revealed that the fragments were specific to Erb-B4. Overall, the WB patterns suggest that in the PSEN mutations, Erb-B4 has a high degree of variation in CT peptide degradation (Figure 7).

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