The effects of different familial Alzheimer’s disease mutations on APP processing in vivo
| Autor: | Henrik Zetterberg, Kaj Blennow, Håkan Thonberg, Maria Eriksdotter, Steinunn Thordardottir, Ove Almkvist, Anne Kinhult Ståhlbom, Caroline Graff |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Heterozygote Neurology Cognitive Neuroscience Clinical Neurology Disease Pathogenesis 03 medical and health sciences Amyloid beta-Protein Precursor 0302 clinical medicine Cerebrospinal fluid Apolipoproteins E Mutation Carrier Alzheimer Disease medicine Amyloid precursor protein PSEN1 Genetics Presenilin-1 Humans Family biology business.industry Research Middle Aged Pathophysiology 030104 developmental biology Cross-Sectional Studies Immunology Mutation biology.protein Neurology (clinical) business Neuroscience Alzheimer’s disease 030217 neurology & neurosurgery Biomarkers |
| Zdroj: | Alzheimer's Research & Therapy |
| ISSN: | 1758-9193 |
| Popis: | Background Disturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer’s disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individuals carrying FAD mutations can give valuable insights into the earliest stages of the disease where therapeutic interventions are thought to be the most effective. Methods In the current cross-sectional study, products of APP processing (e.g., sAPPα, sAPPβ, Aβ38, Aβ40 and Aβ42) were measured in the cerebrospinal fluid (CSF) of individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), as well as in non-mutation carriers from the same families. Results We observed pathological APP processing in presymptomatic carriers of FAD mutations, with different profiles of APP and Aβ isoforms in the three mutation carrier groups, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), except for the well-established decrease in CSF Aβ42 that was found with all mutations. Conclusions These findings add to the current evidence that AD pathophysiology differs between disease-causing mutations and can be monitored in the presymptomatic disease stage by CSF analyses. This may also be important from a therapeutic standpoint, by opening a window to monitor effects of disease-modifying drugs on AD pathophysiology. |
| Databáze: | OpenAIRE |
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