Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations - PubMed (original) (raw)

doi: 10.1186/1750-1326-3-20.

Ian D Daugs, Salvatore Spina, Ruben Vidal, Tyler A Kokjohn, R Lyle Patton, Walter M Kalback, Dean C Luehrs, Douglas G Walker, Eduardo M Castaño, Thomas G Beach, Bernardino Ghetti, Alex E Roher

Affiliations

Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations

Chera L Maarouf et al. Mol Neurodegener. 2008.

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.

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Figures

Figure 1

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.

Figure 2

Figure 2

Histogram depicting the relative amounts of Aβ40 and Aβ42 detected by ELISA. Notice the abundant amount of Aβ40 in the PSEN A431E, V261F, V261I and M146L. The amounts of Aβ40 and Aβ42 were almost equivalent in case F105L. PSEN = presenilin; SAD = Alzheimer's disease; ND = non-demented.

Figure 3

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.

Figure 4

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.

Figure 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.

Figure 6

Figure 6

Western blots of the 80 kDa Notch-1 intracellular domain (NICD) and N-cadherin/CTF2.A) Notice that, with the exception of 3 PSEN mutation cases (Y115C/PSEN1, N141I/PSEN2 and P264L/PSEN1), all the PSEN mutations have reduced quantities of NICD transcription factor. In the SAD cases, there is a heterogeneous distribution of NICD, being almost negligible in one SAD case, elevated in a second case and diminished in the remaining two, relative to the ND controls. B) The amount of N-Cadherin holoprotein detected at 110 kDa is reduced in all PSEN cases relative to the ND controls. A similar pattern is observed for the SAD cases. The N-Cad/CTF2 band at 28 kDa is decreased in all PSEN mutations with the exception of A260V and M146L mutations that displayed higher values. The quantities of the N-Cad/CTF2 were variable in the SAD relative to the ND levels. SAD = sporadic Alzheimer's disease; ND = non-demented.

Figure 7

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.

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References

    1. Kopan R, Goate A. A common enzyme connects notch signaling and Alzheimer's disease. Genes Dev. 2000;14:2799–2806. doi: 10.1101/gad.836900. - DOI - PubMed
    1. Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W. Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway. J Biol Chem. 2006;281:26569–26577. doi: 10.1074/jbc.M600592200. - DOI - PubMed
    1. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999;398:513–517. doi: 10.1038/19077. - DOI - PubMed
    1. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci USA. 2003;100:6382–6387. doi: 10.1073/pnas.1037392100. - DOI - PMC - PubMed
    1. Wolfe MS. The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry. 2006;45:7931–7939. doi: 10.1021/bi060799c. - DOI - PubMed

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