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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 AβPP and N- and C-terminal related peptides. A) The amounts of AβPP holoprotein (110 kDa) and 28 and 25 kDa bands are increased in all PSEN mutations relative to the ND controls. The 110 kDa (AβPP) in SAD is almost equivalent to the ND cases, but is variable with respect to the 28 and 25 kDa bands. B) In our SDS-PAGE system the CT99 and CT83 co-migrate as a single band at ~14 kDa. As can be appreciated, the ND controls have significantly less CT peptides than the PSEN and SAD cases. In addition, AβPP (110 kDa) was variable between the PSEN cases and the ND controls, but was decreased in the SAD cases compared to the ND controls. SAD = sporadic Alzheimer's disease; ND = non-demented.
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Figure 5: Western blots of AβPP and N- and C-terminal related peptides. A) The amounts of AβPP holoprotein (110 kDa) and 28 and 25 kDa bands are increased in all PSEN mutations relative to the ND controls. The 110 kDa (AβPP) in SAD is almost equivalent to the ND cases, but is variable with respect to the 28 and 25 kDa bands. B) In our SDS-PAGE system the CT99 and CT83 co-migrate as a single band at ~14 kDa. As can be appreciated, the ND controls have significantly less CT peptides than the PSEN and SAD cases. In addition, AβPP (110 kDa) was variable between the PSEN cases and the ND controls, but was decreased in the SAD cases compared to the ND controls. SAD = sporadic Alzheimer's disease; ND = non-demented.

Mentions: The N- and C-terminal peptide degradation of AβPP was investigated by WB (Figure 5). The total amount of AβPP (~110 kDa), detected by the 22C11 antibody appears to be approximately increased two-fold among the PSEN mutations compared to ND controls. The total AβPP in SAD cases was the same or slightly elevated than those observed for ND controls (Figure 5A). The 28 and 25 kDa peptide bands were faint in ND cases and significantly elevated in the PSEN mutations in general, suggesting a larger accumulation of N-terminal peptides. A variable amount of N-terminal peptides were observed in SAD cases in relation to those of ND controls. The C-terminal (CT) peptides detected by the CT9APP antibody demonstrated a greater accumulation of the CT99/CT83 bands in PSEN mutations and SAD cases than those observed in ND controls. In contrast, SAD cases showed elevated quantities of CT peptides than those observed in both the ND and PSEN cohorts (Figure 5B). The levels of AβPP were increased compared to CT peptide levels in ND controls and PSEN cases. This ratio was inversed in the SAD group (Figure 5B). Intriguingly, there was a ~40 kDa band that our laboratory has routinely observed in other FAD, SAD, ND controls and transgenic mice which we are presently investigating.


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 AβPP and N- and C-terminal related peptides. A) The amounts of AβPP holoprotein (110 kDa) and 28 and 25 kDa bands are increased in all PSEN mutations relative to the ND controls. The 110 kDa (AβPP) in SAD is almost equivalent to the ND cases, but is variable with respect to the 28 and 25 kDa bands. B) In our SDS-PAGE system the CT99 and CT83 co-migrate as a single band at ~14 kDa. As can be appreciated, the ND controls have significantly less CT peptides than the PSEN and SAD cases. In addition, AβPP (110 kDa) was variable between the PSEN cases and the ND controls, but was decreased in the SAD cases compared to the ND controls. 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 5: Western blots of AβPP and N- and C-terminal related peptides. A) The amounts of AβPP holoprotein (110 kDa) and 28 and 25 kDa bands are increased in all PSEN mutations relative to the ND controls. The 110 kDa (AβPP) in SAD is almost equivalent to the ND cases, but is variable with respect to the 28 and 25 kDa bands. B) In our SDS-PAGE system the CT99 and CT83 co-migrate as a single band at ~14 kDa. As can be appreciated, the ND controls have significantly less CT peptides than the PSEN and SAD cases. In addition, AβPP (110 kDa) was variable between the PSEN cases and the ND controls, but was decreased in the SAD cases compared to the ND controls. SAD = sporadic Alzheimer's disease; ND = non-demented.
Mentions: The N- and C-terminal peptide degradation of AβPP was investigated by WB (Figure 5). The total amount of AβPP (~110 kDa), detected by the 22C11 antibody appears to be approximately increased two-fold among the PSEN mutations compared to ND controls. The total AβPP in SAD cases was the same or slightly elevated than those observed for ND controls (Figure 5A). The 28 and 25 kDa peptide bands were faint in ND cases and significantly elevated in the PSEN mutations in general, suggesting a larger accumulation of N-terminal peptides. A variable amount of N-terminal peptides were observed in SAD cases in relation to those of ND controls. The C-terminal (CT) peptides detected by the CT9APP antibody demonstrated a greater accumulation of the CT99/CT83 bands in PSEN mutations and SAD cases than those observed in ND controls. In contrast, SAD cases showed elevated quantities of CT peptides than those observed in both the ND and PSEN cohorts (Figure 5B). The levels of AβPP were increased compared to CT peptide levels in ND controls and PSEN cases. This ratio was inversed in the SAD group (Figure 5B). Intriguingly, there was a ~40 kDa band that our laboratory has routinely observed in other FAD, SAD, ND controls and transgenic mice which we are presently investigating.

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