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Stem Cell Reports. 2017 Dec 12;9(6):1868-1884. doi: 10.1016/j.stemcr.2017.10.015. Epub 2017 Nov 16.

Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability.

Author information

1
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
2
The New York Stem Cell Foundation Research Institute, New York, NY 10019, USA.
3
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
4
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: tyoung@rics.bwh.harvard.edu.

Abstract

Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aβ, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aβ plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable) and caudal fates (relatively spared) in AD. We find that both the generation of Aβ and the responsiveness of TAU to Aβ are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD.

KEYWORDS:

Abeta; Alzheimer's disease; Tau; amyloid; differential susceptibility; disease modeling; familial AD; iPSCs; neural stem cells; selective vulnerability

PMID:
29153990
PMCID:
PMC5785690
DOI:
10.1016/j.stemcr.2017.10.015
[Indexed for MEDLINE]
Free PMC Article

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