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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

Thioflavin-S histochemistry of leptomeningeal vessels. Whole mounts of leptomeningeal vessels stained by thioflavine-S demonstrating amyloid angiopathy among the different PSEN mutations. A) PSEN1 M146L: moderate; B) PSEN1 V261I: severe; C) PSEN2 N141I: severe. D) PSEN1 V261F: severe; E) PSEN1 A431E: severe; F) PSEN1 Y115C: moderate; G) PSEN1 F105L: severe and H) PSEN1 A260V: moderate-severe. The remaining two PSEN1 mutations A79V and P264L had a mild amyloid deposition (data not shown). Scale Bars = 500 μm.
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Figure 3: Thioflavin-S histochemistry of leptomeningeal vessels. Whole mounts of leptomeningeal vessels stained by thioflavine-S demonstrating amyloid angiopathy among the different PSEN mutations. A) PSEN1 M146L: moderate; B) PSEN1 V261I: severe; C) PSEN2 N141I: severe. D) PSEN1 V261F: severe; E) PSEN1 A431E: severe; F) PSEN1 Y115C: moderate; G) PSEN1 F105L: severe and H) PSEN1 A260V: moderate-severe. The remaining two PSEN1 mutations A79V and P264L had a mild amyloid deposition (data not shown). Scale Bars = 500 μm.

Mentions: Quantification of Aβ levels in the cerebral cortex revealed that in four out of ten PSEN mutations Aβ40 was present in higher amounts than Aβ42 (Table 3 and Figure 2). Presenilin-1 cases with the A431E, V261F, V261I and M146L mutations had Aβ42/Aβ40 ratios of less than 1.00, being more prominent in the former two than in the latter two cases (0.28 and 0.18 versus 0.43 and 0.68). In one case (F105L), the ratio was close to 1:1 (Table 3). A similar pattern was found in two out of four SAD cases (Aβ42/Aβ40 ratios of 0.61 and 0.90). Cortical vascular amyloid in the four PSEN mutation cases cited above had scores of 2, 3, 2 and 1 (Table 2), where the scores 1, 2 and 3 correspond to mild, moderate and severe vascular amyloid deposits, respectively. In addition, three out of these four PSEN cases also had the highest values of CWP with the remaining individual (M146L) having a high number of diffuse deposits (102 per mm2) and mature plaques (14.00 per mm2) (Table 2). With the exception of PSEN cases A79V and P264L, in which very mild cortical vascular amyloid was evident in histological sections, all PSEN cases had mild to moderate amyloid angiopathy in the gray matter. Severe cortical amyloid angiopathy was only seen in the case of V261F. However, examination of isolated leptomeningeal vessels from all PSEN mutation cases demonstrated extensive vascular amyloidosis, as shown in Figure 3, which ranged from moderate (two cases) to moderate/severe (one case) to severe (five cases). In agreement with the cortical vascular amyloid assessment, cases A79V and P264L had negligible amounts of leptomeningeal vascular amyloid (data not shown). The amount of cortical vascular amyloid in the SAD cases ranged from none to moderate. The two ND cases had a mild form of CAA. In addition, we found that within the PSEN cohort positive correlation existed between levels of brain Aβ40 and degree of vascular amyloidosis (R = 0.81).


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)

Thioflavin-S histochemistry of leptomeningeal vessels. Whole mounts of leptomeningeal vessels stained by thioflavine-S demonstrating amyloid angiopathy among the different PSEN mutations. A) PSEN1 M146L: moderate; B) PSEN1 V261I: severe; C) PSEN2 N141I: severe. D) PSEN1 V261F: severe; E) PSEN1 A431E: severe; F) PSEN1 Y115C: moderate; G) PSEN1 F105L: severe and H) PSEN1 A260V: moderate-severe. The remaining two PSEN1 mutations A79V and P264L had a mild amyloid deposition (data not shown). Scale Bars = 500 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Thioflavin-S histochemistry of leptomeningeal vessels. Whole mounts of leptomeningeal vessels stained by thioflavine-S demonstrating amyloid angiopathy among the different PSEN mutations. A) PSEN1 M146L: moderate; B) PSEN1 V261I: severe; C) PSEN2 N141I: severe. D) PSEN1 V261F: severe; E) PSEN1 A431E: severe; F) PSEN1 Y115C: moderate; G) PSEN1 F105L: severe and H) PSEN1 A260V: moderate-severe. The remaining two PSEN1 mutations A79V and P264L had a mild amyloid deposition (data not shown). Scale Bars = 500 μm.
Mentions: Quantification of Aβ levels in the cerebral cortex revealed that in four out of ten PSEN mutations Aβ40 was present in higher amounts than Aβ42 (Table 3 and Figure 2). Presenilin-1 cases with the A431E, V261F, V261I and M146L mutations had Aβ42/Aβ40 ratios of less than 1.00, being more prominent in the former two than in the latter two cases (0.28 and 0.18 versus 0.43 and 0.68). In one case (F105L), the ratio was close to 1:1 (Table 3). A similar pattern was found in two out of four SAD cases (Aβ42/Aβ40 ratios of 0.61 and 0.90). Cortical vascular amyloid in the four PSEN mutation cases cited above had scores of 2, 3, 2 and 1 (Table 2), where the scores 1, 2 and 3 correspond to mild, moderate and severe vascular amyloid deposits, respectively. In addition, three out of these four PSEN cases also had the highest values of CWP with the remaining individual (M146L) having a high number of diffuse deposits (102 per mm2) and mature plaques (14.00 per mm2) (Table 2). With the exception of PSEN cases A79V and P264L, in which very mild cortical vascular amyloid was evident in histological sections, all PSEN cases had mild to moderate amyloid angiopathy in the gray matter. Severe cortical amyloid angiopathy was only seen in the case of V261F. However, examination of isolated leptomeningeal vessels from all PSEN mutation cases demonstrated extensive vascular amyloidosis, as shown in Figure 3, which ranged from moderate (two cases) to moderate/severe (one case) to severe (five cases). In agreement with the cortical vascular amyloid assessment, cases A79V and P264L had negligible amounts of leptomeningeal vascular amyloid (data not shown). The amount of cortical vascular amyloid in the SAD cases ranged from none to moderate. The two ND cases had a mild form of CAA. In addition, we found that within the PSEN cohort positive correlation existed between levels of brain Aβ40 and degree of vascular amyloidosis (R = 0.81).

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