Presenilin 1 Mutants Impair the Self-Renewal and Differentiation of Adult Murine Subventricular Zone-Neuronal Progenitors via Cell-Autonomous Mechanisms Involving Notch Signaling

Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2010; 30(20):6903-15. DOI: 10.1523/JNEUROSCI.0527-10.2010
Source: PubMed


The vast majority of pedigrees with familial Alzheimer's disease (FAD) are caused by inheritance of mutations in the PSEN1 1 gene. While genetic ablation studies have revealed a role for presenilin 1 (PS1) in embryonic neurogenesis, little information has emerged regarding the potential effects of FAD-linked PS1 variants on proliferation, self-renewal and differentiation, key events that control cell fate commitment of adult brain neural progenitors (NPCs). We used adult brain subventricular zone (SVZ)-derived NPC cultures transduced with recombinant lentivirus as a means to investigate the effects of various PS1 mutants on self-renewal and differentiation properties. We now show that viral expression of several PS1 mutants in NPCs leads to impaired self-renewal and altered differentiation toward neuronal lineage, in vitro. In line with these observations, diminished constitutive proliferation and steady-state SVZ progenitor pool size was observed in vivo in transgenic mice expressing the PS1DeltaE9 variant. Moreover, NPC cultures established from the SVZ of adult mice expressing PS1DeltaE9 exhibit reduced self-renewal capacity and premature exit toward neuronal fates. To these findings, we show that both the levels of endogenous Notch/CBF-1-transcriptional activity and transcripts encoding Notch target genes are diminished in SVZ NPCs expressing PS1DeltaE9. The deficits in self-renewal and multipotency are restored by expression of Notch1-ICD or a downstream target of the Notch pathway, Hes1. Hence, we argue that a partial reduction in PS-dependent gamma-secretase processing of the Notch, at least in part, accounts for the impairments observed in SVZ NPCs expressing the FAD-linked PS1DeltaE9 variant.

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    • "The results of -secretase inhibition in this study are difficult to interpret given the non-specificity of action of such inhibitors. In this regard, presenilin-1 mutations have been proposed to affect -secretase processing of Notch, accounting for impairments in self-renewal and altered differentiation toward neuronal lineages in subventricular zone neural progenitor cells expressing the FAD-linked presenilin- 1 DeltaE9 variant [75]. Given that presenilin-1 is one component of the -secretase complex that processes APP and Notch, and that presenilin-1 mutations promote A production [77], these results suggest that presenilin-1 mutations also may induce cell cycle abnormalities via alterations in the processing of APP or Notch. "
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    ABSTRACT: Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition, tau phosphorylation, formation of intracellular neurofibrillary tangles, endoreduplication and related cell cycle events in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. In this insight paper we provide a unifying hypothesis for EOFAD and LOSAD that proposes that the aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell division cycle is a common pathway that explains both early and late-onset forms of AD. Cell cycle abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles, and explain the biochemical (e.g. tau phosphorylation), neuropathological (e.g. neuron hypertrophy; polypoidy) and cognitive changes observed in EOFAD and LOSAD. Genetic mutations in AβPP, PSEN1, and PSEN2 that alter amyloid-β precursor protein and Notch processing drive reactivation of the cell cycle in EOFAD, while age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling and AβPP processing toward the amyloidogenic pathway drives reactivation of the cell cycle in LOSAD. In essence, AβPP and presenilin mutations initiate early, what endocrine dyscrasia initiates later: aberrant cell cycle re-entry of post-mitotic neurons leading to neurodegeneration and cognitive decline in AD. Inhibition of cell cycle re-entry in post-mitotic neurons may be a useful therapeutic strategy to prevent, slow or halt disease progression.
    Full-text · Article · Jul 2015 · Journal of Alzheimer's disease: JAD
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    • "For example, triple transgenic mice (3x Tg-AD) harboring three mutant genes (APP, PSEN1, and tau) develop hippocampal tau-like pathology, β-amyloid plaque deposition, and neurological deficits, and have decreased proliferation associated with the presence of βamyloid plaques and more β-amyloid-containing hippocampal neurons (Rodriguez et al. 2008). Hippocampal neurogenesis is also impaired in transgenic-AD mice harboring single or double mutations of PSEN1 or APP, including reduced progenitor cell proliferation, survival, and neuronal differentiation (Wang et al. 2004; Wen et al. 2004; Donovan et al. 2006; Choi et al. 2008; Ermini et al. 2008; Demars et al. 2010; Veeraraghavalu et al. 2010). Tau protein – a microtubule-associated protein that stabilizes neuronal axons in the hippocampus under physiological conditions – is reduced in AD mouse models that also have reduced neurogenesis (Llorens-Martin et al. 2012). "
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    ABSTRACT: With the growth of the aging population and increasing life expectancy, the diagnosis of age-related neurodegenerative diseases is predicted to increase 12% by 2030. There is urgent need to develop better and novel treatments for disorders like Alzheimer's, Huntington's, and Parkinson's diseases. As these neurodegenerative diseases are customarily defined by the progressive loss of neurons, treatment strategies have traditionally focused on replacing neurons lost during disease progression. To this end, the self-renewing and multipotent properties of neural stem/precursor cells (NSPCs) that exist in the adult brain suggest that NSPCs could contribute to a therapy for replacement of damaged or lost neurons. Although a wealth of research demonstrates the proof-of-concept that NSPC transplantation has therapeutic potential, there are considerable barriers between the theory of cell transplantation and clinical implementation. However, a new view on harnessing the power of NSPC for treatment of neurodegenerative disorders has emerged, and focuses on treating neuropathological aspects of the disease prior to the appearance of overt neuronal loss. For example, rather than merely replacing lost neurons, NSPCs are now being considered for their ability to provide trophic support. Here we review the evolution of how the field has considered application of NSPCs for treatment of neurodegeneration disorders. We discuss the challenges posed by the "traditional" view of neurodegeneration - overt cell loss - for utilization of NSPCs for treatment of these disorders. We also review the emergence of an alternative strategy that involves fine-tuning the neurogenic capacity of existing adult NSPCs so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. We conclude with our opinion that for this strategy to become a translational reality, it requires a thorough understanding of NSPCs, the dynamic process of adult neurogenesis, and a better understanding of the pathological trajectory of each neurodegenerative disease.
    Full-text · Article · Mar 2015
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    • "For instance, it is possible that unknown genes transcriptionally regulated in vivo by the AICD might influence Aβ metabolism in return. In support to these views, Veeraraghavalu and colleagues recently demonstrated that Notch signalling was impaired in transgenic mice overexpressing PS1 mutants, albeit in the presence of endogenous PS1-WT and all APH1 isoforms [56]. They found decreased self-renewal and differentiation of neuronal precursor cells in the subventricular zone, suggesting that the loss-of-function phenotype of PSEN1 mutations can also be observed in heterogeneous conditions. "
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