Cortical development in the presenilin‐1 null mutant mouse fails after splitting of the preplate and is not due to a failure of reelin‐dependent signaling

Gasperi, Rita De; Sosa, Miguel A. Gama; Wen, Paul; Li, Jingjun; Perez, Gissel M.; Curran, Tom; Elder, Gregory A.

doi:10.1002/dvdy.21661

Cited by 9 publications

(6 citation statements)

References 61 publications

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“…The potential modulation of the reelin signaling pathway by γ‐secretase has been explored in conventional PS1 KO mice (43). In that work, no difference in reelin levels was observed between embryonic PS1 ‐null mutant and wild‐type mice.…”

Section: Discussionmentioning

confidence: 99%

ApoER2 processing by presenilin‐1 modulates reelin expression

et al. 2013

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The reelin signaling protein and its downstream components have been associated with synaptic plasticity and neurotransmission. The reelin signaling pathway begins with the binding of reelin to the transmembrane lipoprotein receptor apolipoprotein E receptor 2 (ApoER2), which in turns induces the sequential cleavage of ApoER2 by the sequential action of α- and γ-secretases. Using conditional-knockout mice of the catalytic component of the γ-secretase complex, presenilin 1 (PS1), we demonstrated increased brain ApoER2 and reelin protein and transcript levels, with no changes in the number of reelin-positive cells. Using the human SH-SY5Y neuroblastoma cell line, we showed that ApoER2 processing occurs in the presence of PS1, producing an intracellular ApoER2 C-terminal fragment. In addition, the pharmacologic inhibition of γ-secretase in SH-SY5Y cells led to increased reelin levels. Overexpression of ApoER2 decreased reelin mRNA levels in these cells. A luciferase reporter gene assay and nuclear fractionation confirmed that increased amounts of intracellular fragment of ApoER2 suppressed reelin expression at a transcriptional level. Chromatin immunoprecipitation experiments corroborated that the intracellular fragment of ApoER2 bound to the RELN promoter region. Our study suggests that PS1/γ-secretase-dependent processing of the reelin receptor ApoER2 inhibits reelin expression and may regulate its signaling.

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Section: Discussionmentioning

confidence: 99%

ApoER2 processing by presenilin‐1 modulates reelin expression

et al. 2013

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“…Primary neuronal cultures were prepared from the cerebral cortex isolated from E15.5-16 embryos as previously described [ 86 , 87 ] and maintained in Neurobasal medium/B27 supplement (Invitrogen) for 5-7 days in vitro (DIV). For treatment with insulin or IGF-1, neurons were maintained overnight in neurobasal medium devoid of B27 supplement and then treated as described above.…”

Section: Methodsmentioning

confidence: 99%

Presenilin-1 regulates induction of hypoxia inducible factor-1α: altered activation by a mutation associated with familial Alzheimer's disease

Gasperi

Sosa

Dracheva

et al. 2010

Mol Neurodegeneration

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BackgroundMutations in presenilin-1 (Psen1) cause familial Alzheimer's disease (FAD). Both hypoxia and ischemia have been implicated in the pathological cascade that leads to amyloid deposition in AD. Here we investigated whether Psen1 might regulate hypoxic responses by modulating induction of the transcription factor hypoxia inducible factor 1-α (HIF-1α).ResultsIn fibroblasts that lack Psen1 induction of HIF-1α was impaired in response to the hypoxia mimetic cobalt chloride, as well as was induction by insulin and calcium chelation. Reintroduction of human Psen1 using a lentiviral vector partially rescued the responsiveness of Psen1-/- fibroblasts to cobalt chloride induction. HIF-1α induction did not require Psen1's associated γ-secretase activity. In addition, the failure of insulin to induce HIF-1α was not explicable on the basis of failed activation of the phosphatidylinositol 3-kinase (PI3K/Akt) pathway which activated normally in Psen1-/- fibroblasts. Rather we found that basal levels of HIF-1α were lower in Psen1-/- fibroblasts and that the basis for lower constitutive levels of HIF-1α was best explained by accelerated HIF-1α degradation. We further found that Psen1 and HIF-1α physically interact suggesting that Psen1 may protect HIF-1α from degradation through the proteasome. In fibroblasts harboring the M146V Psen1 FAD mutation on a mouse Psen1 null background, metabolic induction of HIF-1α by insulin was impaired but not hypoxic induction by cobalt chloride. Unlike Psen1-/- fibroblasts, basal levels of HIF-1α were normal in FAD mutant fibroblasts but activation of the insulin-receptor pathway was impaired. Interestingly, in Psen1-/- primary neuronal cultures HIF-1α was induced normally in response to cobalt chloride but insulin induction of HIF-1α was impaired even though activation of the PI3K/Akt pathway by insulin proceeded normally in Psen1-/- neuronal cultures. Basal levels of HIF-1α were not significantly different in Psen1-/- neurons and HIF-1α levels were normal in Psen1-/- embryos.ConclusionsCollectively these studies show that Psen1 regulates induction of HIF-1α although they indicate that cell type specific differences exist in the effect of Psen1 on induction. They also show that the M146V Psen1 FAD mutation impairs metabolic induction of HIF-1α, an observation that may have pathophysiological significance for AD.

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“…In contrast, Reelin signaling seems to be intact in primary neuronal cultures obtained from mice with null expression of the gene for presenilin-1 (PSEN-1 -/- ), which is the catalytic subunit of gamma-secretase [ 72 ]. As well, PSEN-1 is not required for Reelin-induced phosphorylation of Dab1 [ 52 , 73 , 74 ].…”

Section: Ldl Receptor Interactors In Normal and Pathological Brain Co...mentioning

confidence: 99%

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System

Passarella

Ronci

Liberto

et al. 2022

IJMS

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Recent studies have highlighted the mechanisms controlling the formation of cerebral cholesterol, which is synthesized in situ primarily by astrocytes, where it is loaded onto apolipoproteins and delivered to neurons and oligodendrocytes through interactions with specific lipoprotein receptors. The “cholesterol shuttle” is influenced by numerous proteins or carbohydrates, which mainly modulate the lipoprotein receptor activity, function and signaling. These molecules, provided with enzymatic/proteolytic activity leading to the formation of peptide fragments of different sizes and specific sequences, could be also responsible for machinery malfunctions, which are associated with neurological, neurodegenerative and neurodevelopmental disorders. In this context, we have pointed out that purines, ancestral molecules acting as signal molecules and neuromodulators at the central nervous system, can influence the homeostatic machinery of the cerebral cholesterol turnover and vice versa. Evidence gathered so far indicates that purine receptors, mainly the subtypes P2Y2, P2X7 and A2A, are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s and Niemann–Pick C diseases, by controlling the brain cholesterol homeostasis; in addition, alterations in cholesterol turnover can hinder the purine receptor function. Although the precise mechanisms of these interactions are currently poorly understood, the results here collected on cholesterol–purine reciprocal control could hopefully promote further research.

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Cortical development in the presenilin‐1 null mutant mouse fails after splitting of the preplate and is not due to a failure of reelin‐dependent signaling

Cited by 9 publications

References 61 publications

ApoER2 processing by presenilin‐1 modulates reelin expression

ApoER2 processing by presenilin‐1 modulates reelin expression

Presenilin-1 regulates induction of hypoxia inducible factor-1α: altered activation by a mutation associated with familial Alzheimer's disease

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System

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