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Hum Mol Genet. 2014 Dec 15;23(24):6512-27. doi: 10.1093/hmg/ddu370. Epub 2014 Jul 15.

Deficiency of patched 1-induced Gli1 signal transduction results in astrogenesis in Swedish mutated APP transgenic mice.

Author information

1
Center for Advanced Therapeutic Strategies for Brain Disorders and.
2
Novartis Pharm Ltd, Nervous System Research, Basel CH-4002, Switzerland and.
3
Center for Hormone Advanced Science and Education, The Roskamp Institute, Sarasota, FL 34243, USA, yshen@rfdn.org rli@rfdn.org.
4
Center for Advanced Therapeutic Strategies for Brain Disorders and, Department of Neurology, University of Florida College of Medicine, Gainesville FL32610, USA yshen@rfdn.org rli@rfdn.org.

Abstract

Normally, sonic hedgehog (Shh) signaling induces high levels of Patched 1 (Ptc1) and its associated transcription factor Gli1 with genesis of specific neuronal progeny. But their roles in the neural stem cells (NSCs), including glial precursor cells (GPCs), of Alzheimer's disease (AD) are unclear. Here, we show that Ptc1 and Gli1 are significantly deficits in the hippocampus of an aged AD transgenic mouse mode, whereas these two molecules are highly elevated at young ages. Our similar findings in autopsied AD brains validate the discovery in AD mouse models. To examine whether Aβ peptides, which are a main component of the amyloid plaques in AD brains, affected Ptc1-Gli1 signaling, we treated GPCs with Aβ peptides, we found that high dose of Aβ1-42 but not Aβ1-40 significantly decreased Ptc1-Gli1, while Shh itself was elevated in hippocampal NSCs/GPCs. Furthermore, we found that deficits of Ptc1-Gli1 signaling induced NSCs/GPCs into asymmetric division, which results in an increase in the number of dividing cells including transit-amplifying cells and neuroblasts. These precursor cells commit to apoptosis-like death under the toxic conditions. By this way, adult neural precursor cell pool is exhausted and defective neurogenesis happens in AD brains. Our findings suggest that Ptc1-Gli1 signaling deregulation resulting abnormal loss of GPCs may contribute to a cognition decline in AD brains. The novel findings elucidate a new molecular mechanism of adult NSCs/GPCs on neurogenesis and demonstrate a regulatory role for Ptc1-Gli1 in adult neural circuit integrity of the brain.

PMID:
25027328
PMCID:
PMC4296204
DOI:
10.1093/hmg/ddu370
[Indexed for MEDLINE]
Free PMC Article

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