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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 soluble tau isoforms quantified by scanning densitometry. The overall quantities of soluble tau isoforms substantially varied among the different PSEN mutations and SAD cases and from the ND controls. Most of the tau proteins were concentrated between ~60–40 kDa. In general there was more tau protein in the PSEN mutations than in the ND controls. There were prominent bands at ~100–110 kDa in 7 out of 10 PS mutations that were absent in the ND controls. Likewise, this band was seen in 3 out of 4 of the SAD cases and not in the ND controls. These bands may correspond to dimeric forms of tau. SAD = sporadic Alzheimer's disease; ND = non-demented.
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Figure 4: Western blots of soluble tau isoforms quantified by scanning densitometry. The overall quantities of soluble tau isoforms substantially varied among the different PSEN mutations and SAD cases and from the ND controls. Most of the tau proteins were concentrated between ~60–40 kDa. In general there was more tau protein in the PSEN mutations than in the ND controls. There were prominent bands at ~100–110 kDa in 7 out of 10 PS mutations that were absent in the ND controls. Likewise, this band was seen in 3 out of 4 of the SAD cases and not in the ND controls. These bands may correspond to dimeric forms of tau. SAD = sporadic Alzheimer's disease; ND = non-demented.

Mentions: Tau antibody probing revealed a series of bands with a range of ~110 to ~28 kDa (Figure 4), representing both normal and PHF-tau [62]. In seven out of ten PSEN mutations there were bands that corresponded to dimeric forms of tau (~100–110 kDa). In general, the PSEN mutations demonstrated elevated amounts of soluble tau protein relative to the ND controls, the exception being the ~28 and ~57 kDa bands (Figure 4). The PSEN A79V and V261I mutations revealed low NFT counts on neuropathological examination (Table 2), and on WB had relatively moderate amounts of soluble tau peptides and were missing the ~100–110 kDa (dimeric) peptides (Figure 4). The case with the A260V mutation, which also was missing the ~100–110 kDa peptides, had an average amount NFT (31.00 per mm2) (Table 2). The PSEN cases with the highest NFT scores (A431E, V261F, and N141I; Table 2) also had the highest levels of dimeric tau as observed by WB (Figure 4).


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 soluble tau isoforms quantified by scanning densitometry. The overall quantities of soluble tau isoforms substantially varied among the different PSEN mutations and SAD cases and from the ND controls. Most of the tau proteins were concentrated between ~60–40 kDa. In general there was more tau protein in the PSEN mutations than in the ND controls. There were prominent bands at ~100–110 kDa in 7 out of 10 PS mutations that were absent in the ND controls. Likewise, this band was seen in 3 out of 4 of the SAD cases and not in the ND controls. These bands may correspond to dimeric forms of tau. 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 4: Western blots of soluble tau isoforms quantified by scanning densitometry. The overall quantities of soluble tau isoforms substantially varied among the different PSEN mutations and SAD cases and from the ND controls. Most of the tau proteins were concentrated between ~60–40 kDa. In general there was more tau protein in the PSEN mutations than in the ND controls. There were prominent bands at ~100–110 kDa in 7 out of 10 PS mutations that were absent in the ND controls. Likewise, this band was seen in 3 out of 4 of the SAD cases and not in the ND controls. These bands may correspond to dimeric forms of tau. SAD = sporadic Alzheimer's disease; ND = non-demented.
Mentions: Tau antibody probing revealed a series of bands with a range of ~110 to ~28 kDa (Figure 4), representing both normal and PHF-tau [62]. In seven out of ten PSEN mutations there were bands that corresponded to dimeric forms of tau (~100–110 kDa). In general, the PSEN mutations demonstrated elevated amounts of soluble tau protein relative to the ND controls, the exception being the ~28 and ~57 kDa bands (Figure 4). The PSEN A79V and V261I mutations revealed low NFT counts on neuropathological examination (Table 2), and on WB had relatively moderate amounts of soluble tau peptides and were missing the ~100–110 kDa (dimeric) peptides (Figure 4). The case with the A260V mutation, which also was missing the ~100–110 kDa peptides, had an average amount NFT (31.00 per mm2) (Table 2). The PSEN cases with the highest NFT scores (A431E, V261F, and N141I; Table 2) also had the highest levels of dimeric tau as observed by WB (Figure 4).

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