Selective expression of presenilin 1 in neural progenitor cells rescues the cerebral hemorrhages and cortical lamination defects in presenilin 1-null mutant mice
Open accessAbstract
Mice with a null mutation of the presenilin 1 gene(Psen1–/–) die during late intrauterine life or shortly after birth and exhibit multiple CNS and non-CNS abnormalities,including cerebral hemorrhages and altered cortical development. The cellular and molecular basis for the developmental effects of Psen1 remain incompletely understood. Psen1 is expressed in neural progenitors in developing brain, as well as in postmitotic neurons. We crossed transgenic mice with either neuron-specific or neural progenitor-specific expression of Psen1 onto the Psen1–/– background. We show that neither neuron-specific nor neural progenitor-specific expression of Psen1 can rescue the embryonic lethality of the Psen1–/–embryo. Indeed neuron-specific expression rescued none of the abnormalities in Psen1–/– mice. However, Psen1 expression in neural progenitors rescued the cortical lamination defects, as well as the cerebral hemorrhages, and restored a normal vascular pattern in Psen1–/– embryos. Collectively, these studies demonstrate that Psen1 expression in neural progenitor cells is crucial for cortical development and reveal a novel role for neuroectodermal expression of Psen1 in development of the brain vasculature.
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Hemorrhages and vascular abnormalities in PSEN1-/- mice can be corrected by neuron-specific PSEN1 expression.
“Interestingly, hemorrhages and vascular abnormalities in PSEN1 -/ -mice can be corrected by neuron-specific PSEN1 expression (641), suggesting that impaired vascular-neuronal cross-talk contributes to vascular pathophysiology (191, 641).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [641]
The Abstract states that neuron-specific Psen1 expression rescued none of the abnormalities in Psen1-null mice. The Discussion says instead that neural progenitor-specific expression eliminated CNS hemorrhages and rescued vascular defects. (LLM, conf=0.95)
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Experimental — accuracy not yet measuredPSEN1-/- mice exhibit severe microbleeds and endothelial degeneration in the neocortex at embryonic day 18.5.
“Additionally, PSEN1 -/ -mice exhibit severe microbleeds and endothelial degeneration in the neocortex at embryonic day 18.5 (641), indicating that PSEN1 loss of function induces BBB damage.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [641]
The section on restoring normal vasculature reports that intracerebral hemorrhages are invariably present in Psen1-null embryos at E18.5 and that vessels in the cerebral hemispheres appear distorted. It does not characterize the hemorrhages as severe neocortical microbleeds or establish endothelial degeneration in those embryos; the Discussion attributes endothelial apoptosis and necrosis to a prior study. No page number is available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPSEN1 mutant and knockout transgenic models that are not crossed with APP models exhibit significant vascular pathology such as BBB breakdown, hemorrhages, and loss of pericytes.
“Furthermore, PSEN1 mutant and knockout transgenic models that are not crossed with APP models exhibit significant vascular pathology such as BBB breakdown, hemorrhages, and loss of pericytes (191, 641)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [641]
The section on restoring normal vasculature reports intracerebral and intraventricular hemorrhages and distorted vessels in Psen1-null embryos. It does not report BBB breakdown or loss of pericytes; its mention of pericytes describes their normal role in vascular development. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVascular dysfunction caused by PSEN1 mutations can develop independent of amyloid pathology.
“suggesting that vascular dysfunction caused by PSEN1 mutations can develop independent of amyloid pathology.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [641]
The section on restoring normal vasculature reports abnormal vessels and hemorrhages in Psen1-null mouse embryos, with vascular changes reversed by Psen1 expression in neural progenitors. This supports a role for Psen1 in vascular development, but the paper does not assess amyloid pathology or establish independence from it; its embryos also carry a null mutation rather than a disease-associated PSEN1 mutation. (LLM, conf=0.84)
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References 51 · Cited by 30
Research works printed but not linked: 2
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- O'Gorman, S., Dagenais, N. A., Qian, M. and Marchuk, Y. (1997). Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germline of mice, but not in embryonic stem cells. Proc. Natl. Acad. Sci. USA 94, 14602-14607.
- Authors
- Wen, P. H., De Gasperi, R., Sosa, M. A. G., Rocher, A. B., Friedrich, V. L., Hof, P. R., & Elder, G. A.
- Affiliations
- James J. Peters VA Medical Center (US)
- Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029,USA
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Elder, Gregory A.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2005-09-01
- Volume
- 132
- Issue
- 17
- Pages
- 3873-3883
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC1698506
- OpenAlex
- W2065712407
- Cited by
- 30
- References
- 51
- Citations by year
- 2026: 1 · 2022: 4 · 2020: 2 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 0.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (AG05138, AG02219)
- National Institute on Aging (AG-02219, AG23599, AG 05138, P50AG005138, R03AG021305, R21AG023599, AG20139, AG21305, P01AG002219, R01AG020139)
- National Institute of Mental Health (R03MH070603, R01MH064673, MH70603)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- presenilin 1, neural progenitor cells, cerebral hemorrhage, cortical development, transgenic rescue, embryonic lethality, neuroectoderm
- MeSH terms
- Animals, Cell Movement, Cerebral Cortex, Cerebral Hemorrhage, Embryo, Mammalian, Humans, Intermediate Filament Proteins, Introns, Membrane Proteins, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Stem Cells, Telencephalon, Gene Expression Regulation, Developmental, Embryo Loss, Endothelial Cells, Mice, Rats, Presenilin-1, Nestin
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