Artikel
Neuropathological differences between familial Alzheimer’s disease (FAD) caused by Presenilin mutation E280A and sporadic Alzheimer’s disease (SAD)
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Autoren
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Diego Sepulveda-Falla
- University Medical Center Hamburg-Eppendorf, Institute of Neuropathology, Hamburg, Germany
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Felix Dinkel
- University Medical Center Hamburg-Eppendorf, Institute of Neuropathology, Hamburg, Germany
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Frank Dohler
- University Medical Center Hamburg-Eppendorf, Institute of Neuropathology, Hamburg, Germany
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Christian Hagel
- University Medical Center Hamburg-Eppendorf, Institute of Neuropathology, Hamburg, Germany
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Francisco Lopera
- University of Antioquia, Neuroscience Group of Antioquia, Faculty of Medicine, Medellin, Colombia
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Markus Glatzel
- University Medical Center Hamburg-Eppendorf, Institute of Neuropathology, Hamburg, Germany
| Veröffentlicht: | 25. August 2015 |
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Gliederung
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Introduction: Even though less than 1% of Alzheimer’s disease (AD) is of hereditary origin, FAD is used as a reference for its natural history and as a framework for the development of animal models and therapies for the disease. Given that all known mutations for FAD occur in proteins involved in the generation of beta amyloid (Ab) from APP and amyloid aggregation is considered to be a fundamental step in the etiology of AD, using FAD as a model for the disease seems to be logical. Nevertheless, recent findings show pathophysiological differences. Here we explore the neuropathological profile of both AD variants further.
Objectives: To assess differences in neuropathological profiles of PS1 FAD and SAD.
Materials and methods: Formalin preserved and frozen brain tissue from 23 PS1E280A and 10 SAD cases were studied histologically and biochemically for known hallmarks of AD such as Ab aggregates, hyperphosphorylated Tau (pTau) aggregates and TDP43. All studied cases were previously characterized as CERAD C and with Braak stage V or higher. Pathology was histologically assessed in five different brain regions for all markers. Frontal cortex was chosen for Ab biochemical studies.
Results: We found that there were not relevant differences in severity or distribution of amyloid plaques and beta amyloid immunosignal between PS1E280A FAD and SAD. Both variant show higher Ab pathology in frontal cortex. These region was used for further characterization of different Ab lengths. We observed significant higher Ab 1-38 and 1-43 together with lower 1-42 in SAD when compared with PS1E280A FAD cases. Ab 1-38 and 1-42 differences were confirmed biochemically by ELISA. Regarding pTau pathology, only occipital cortex and cerebellum showed higher immunosignal in FAD cases and regional distribution varied individually between FAD and SAD cases. Finally, nearly half of SAD cases showed phospho-TDP43 pathology while none of PS1E280A did.
Conclusion: Summing up with previous results, we have identified several pathological differences between FAD and SAD that indicate that PS1 FAD may not be a pathological model for all SAD cases and these differences should be explored further.
Figure 1 [Fig. 1]
