Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network

Celeste M Karch,Alice Pébay,Damián Hernández,Jacob Marsh,Denise Levitch,Carlos Cruchaga,Jen‐Chyong Wang ,Sarah B Berman ,Jasmeer P Chhatwal ,Martin R Farlow ,John C Morris,Bernardino Ghetti,Wendy Sigurdson,Joanne Norton,Randall J Bateman,Tamara Donahue,Simon Hsu,Alex W Hewitt,Alison Goate

doi:10.1186/s13195-018-0400-0

Abstract

BackgroundMutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. However, understanding of the basic biological mechanisms that drive the disease are limited. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease.ResultsWe generated a library of 98 dermal fibroblast lines from 42 ADAD families enrolled in DIAN. We have reprogrammed a subset of the DIAN fibroblast lines into patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized for pluripotency markers.ConclusionsThis library represents a comprehensive resource that can be used for disease modeling and the development of novel therapeutics.

Highlights

Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD)
We present a resource of patient-specific fibroblast and induced pluripotent stem cell lines carrying APP, PSEN1, or PSEN2 mutations and noncarrier, related controls. iPSCs have emerged as a powerful system for studying the molecular mechanisms underlying neurodegenerative diseases [23,24,25,26,27]
A total of 98 fibroblast lines are represented by 51 APP, PSEN1, or PSEN2 mutation carriers and 47 non-carriers, related family members from 42 families (Fig. 1, Table 1)

Summary

Introduction

Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease. Inherited mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) cause early-onset Alzheimer disease (AD) [1, 2]. The amyloid cascade hypothesis proposes that changes in APP and/or Aβ homeostasis lead to the aggregation of Aβ and Dominantly inherited mutations in APP account for approximately 16% of ADAD, represented by 30 pathogenic mutations [7].

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Discussion

Conclusion