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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

Histology and immunocytochemistry of amyloid deposits in PSEN mutations. A) PSEN2 N141I mutation primitive plaques immunoreacted with 10D5 antibody. B) Cotton wool plaques in the PSEN1 A431E mutation immunoreacted with the 21F12. On the upper-right corner there is a mature plaque. C) Cotton wool plaques associated with the PSEN1 A260V mutation immunoreacted with the 10D5 antibody. D) Mature neuritic plaque observed in the PSEN1 A79V mutation. 10D5 antibody. E) Primitive plaque localized the cerebral cortex of the PSEN1 A79V mutation immunoreacted with the 10D5 antibody. F) Cortical amyloid plaques immunoreacted with the 10D5 antibodies at low magnification in the PSEN1 V261F mutation. Numerous CWP and occasional mature core neuritic plaques are observed in addition to severe amyloid angiopathy. G) Cotton wool plaques in the PSEN1 V261F mutation developed with the 10D5 antibody. H) Abundant CWP observed in the PSEN1 V261F stained by hematoxilin and eosin. The plaques are surrounded by a discreet number of reactive astrocytes. In the remaining areas of the field several regions of severe neuronal loss and glyosis and moderate microvacuolization are observed. I) Severe Aβ immunoreactive cerebral amyloid angiopathy in the cerebral cortex of PSEN1 A431E mutation. J) A hematoxylin and eosin stained section of the cerebral cortex of PS1 431E mutation. Magnifications: 63 × (A, B, C, D, E, G); 40 × (I and J); 20 × (H) and 10 × (F). Scale Bars = 20 μm.
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Figure 1: Histology and immunocytochemistry of amyloid deposits in PSEN mutations. A) PSEN2 N141I mutation primitive plaques immunoreacted with 10D5 antibody. B) Cotton wool plaques in the PSEN1 A431E mutation immunoreacted with the 21F12. On the upper-right corner there is a mature plaque. C) Cotton wool plaques associated with the PSEN1 A260V mutation immunoreacted with the 10D5 antibody. D) Mature neuritic plaque observed in the PSEN1 A79V mutation. 10D5 antibody. E) Primitive plaque localized the cerebral cortex of the PSEN1 A79V mutation immunoreacted with the 10D5 antibody. F) Cortical amyloid plaques immunoreacted with the 10D5 antibodies at low magnification in the PSEN1 V261F mutation. Numerous CWP and occasional mature core neuritic plaques are observed in addition to severe amyloid angiopathy. G) Cotton wool plaques in the PSEN1 V261F mutation developed with the 10D5 antibody. H) Abundant CWP observed in the PSEN1 V261F stained by hematoxilin and eosin. The plaques are surrounded by a discreet number of reactive astrocytes. In the remaining areas of the field several regions of severe neuronal loss and glyosis and moderate microvacuolization are observed. I) Severe Aβ immunoreactive cerebral amyloid angiopathy in the cerebral cortex of PSEN1 A431E mutation. J) A hematoxylin and eosin stained section of the cerebral cortex of PS1 431E mutation. Magnifications: 63 × (A, B, C, D, E, G); 40 × (I and J); 20 × (H) and 10 × (F). Scale Bars = 20 μm.

Mentions: A quantitative comparison of the different type and number of neuropathological findings in the cerebral cortex of the PSEN mutation cases and the SAD cases is given in Table 2. A representative display of their morphology is shown in Figure 1. Cotton-wool plaques (CWP) were the most abundant type of Aβ deposit in four cases of PSEN1 mutations: A431E, V261F, V261I and P264L. They were observed throughout the cortical layers, although they were more abundant in the upper layers. The diameter of these plaques varied from an average of 80–90 μm in A431E, V261F and P264L cases to 145 μm in the V261I case. Their mean frequency was approximately 40–50 plaques/mm2 in the A431E, V261F and V261I mutations. The P264L mutation case displayed a reduced number of CWP (average of 14/mm2), consistent with its overall reduced burden of Aβ deposition compared to that of the remaining cases. No CWP were observed in the superior frontal and cingulate gyri in the SAD group and in the cases with the PSEN1 mutations: A79V, A260V, F105L, Y115C and M146L and the PSEN2 N141I mutation.


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)

Histology and immunocytochemistry of amyloid deposits in PSEN mutations. A) PSEN2 N141I mutation primitive plaques immunoreacted with 10D5 antibody. B) Cotton wool plaques in the PSEN1 A431E mutation immunoreacted with the 21F12. On the upper-right corner there is a mature plaque. C) Cotton wool plaques associated with the PSEN1 A260V mutation immunoreacted with the 10D5 antibody. D) Mature neuritic plaque observed in the PSEN1 A79V mutation. 10D5 antibody. E) Primitive plaque localized the cerebral cortex of the PSEN1 A79V mutation immunoreacted with the 10D5 antibody. F) Cortical amyloid plaques immunoreacted with the 10D5 antibodies at low magnification in the PSEN1 V261F mutation. Numerous CWP and occasional mature core neuritic plaques are observed in addition to severe amyloid angiopathy. G) Cotton wool plaques in the PSEN1 V261F mutation developed with the 10D5 antibody. H) Abundant CWP observed in the PSEN1 V261F stained by hematoxilin and eosin. The plaques are surrounded by a discreet number of reactive astrocytes. In the remaining areas of the field several regions of severe neuronal loss and glyosis and moderate microvacuolization are observed. I) Severe Aβ immunoreactive cerebral amyloid angiopathy in the cerebral cortex of PSEN1 A431E mutation. J) A hematoxylin and eosin stained section of the cerebral cortex of PS1 431E mutation. Magnifications: 63 × (A, B, C, D, E, G); 40 × (I and J); 20 × (H) and 10 × (F). Scale Bars = 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Histology and immunocytochemistry of amyloid deposits in PSEN mutations. A) PSEN2 N141I mutation primitive plaques immunoreacted with 10D5 antibody. B) Cotton wool plaques in the PSEN1 A431E mutation immunoreacted with the 21F12. On the upper-right corner there is a mature plaque. C) Cotton wool plaques associated with the PSEN1 A260V mutation immunoreacted with the 10D5 antibody. D) Mature neuritic plaque observed in the PSEN1 A79V mutation. 10D5 antibody. E) Primitive plaque localized the cerebral cortex of the PSEN1 A79V mutation immunoreacted with the 10D5 antibody. F) Cortical amyloid plaques immunoreacted with the 10D5 antibodies at low magnification in the PSEN1 V261F mutation. Numerous CWP and occasional mature core neuritic plaques are observed in addition to severe amyloid angiopathy. G) Cotton wool plaques in the PSEN1 V261F mutation developed with the 10D5 antibody. H) Abundant CWP observed in the PSEN1 V261F stained by hematoxilin and eosin. The plaques are surrounded by a discreet number of reactive astrocytes. In the remaining areas of the field several regions of severe neuronal loss and glyosis and moderate microvacuolization are observed. I) Severe Aβ immunoreactive cerebral amyloid angiopathy in the cerebral cortex of PSEN1 A431E mutation. J) A hematoxylin and eosin stained section of the cerebral cortex of PS1 431E mutation. Magnifications: 63 × (A, B, C, D, E, G); 40 × (I and J); 20 × (H) and 10 × (F). Scale Bars = 20 μm.
Mentions: A quantitative comparison of the different type and number of neuropathological findings in the cerebral cortex of the PSEN mutation cases and the SAD cases is given in Table 2. A representative display of their morphology is shown in Figure 1. Cotton-wool plaques (CWP) were the most abundant type of Aβ deposit in four cases of PSEN1 mutations: A431E, V261F, V261I and P264L. They were observed throughout the cortical layers, although they were more abundant in the upper layers. The diameter of these plaques varied from an average of 80–90 μm in A431E, V261F and P264L cases to 145 μm in the V261I case. Their mean frequency was approximately 40–50 plaques/mm2 in the A431E, V261F and V261I mutations. The P264L mutation case displayed a reduced number of CWP (average of 14/mm2), consistent with its overall reduced burden of Aβ deposition compared to that of the remaining cases. No CWP were observed in the superior frontal and cingulate gyri in the SAD group and in the cases with the PSEN1 mutations: A79V, A260V, F105L, Y115C and M146L and the PSEN2 N141I mutation.

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