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Amyloid β Peptide Compromises Neural Stem Cell Fate by Irreversibly Disturbing Mitochondrial Oxidative State and Blocking Mitochondrial Biogenesis and Dynamics

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by the accumulation of amyloid β peptide (Aβ). Although most AD mouse models present a decline in neurogenesis, they express mutated genes which regulate neurogenesis per se and are not present in most AD patients, thus masking the real impact of Aβ on adult neurogenesis. Mitochondrion, a well-known target of Aβ in neurons, is a main regulator of neural stem cell (NSC) fate. Here, we aimed to investigate the impact of Aβ on NSC mitochondria and cell fate decisions, namely whether and how Aβ affects neurogenesis. NSC fate and mitochondrial parameters, including biogenesis, dynamics, and oxidative stress, were evaluated. Our results showed that Aβ impaired NSC viability and proliferation and indirectly blocked neurogenic differentiation, by disrupting mitochondrial signaling of self-renewing NSCs. Importantly, Aβ decreased ATP levels, generated oxidative stress, and affected the radical scavenger system through SOD2 and SIRT3. Aβ also reduced mtDNA and mitochondrial biogenesis proteins, such as Tfam, PGC-1α, and NRF1, and inhibited activation of PGC-1α-positive regulator CREB. Moreover, Aβ triggered mitochondrial fragmentation in self-renewing NSCs and reduced mitochondrial fusion proteins, such as Mfn2 and ERRα. Notably, Aβ compromised NSC commitment and survival by irreversibly impairing mitochondria and thwarting any neurogenic rescue through mitochondrial biogenesis, dynamics, or radical scavenger system. Altogether, this study brings new perspective to rethink the molecular targets relevant for endogenous NSC-based strategies in AD.

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Abbreviations

Aβ:

Amyloid β

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

BrdU:

Bromodeoxyuridine

CREB:

cAMP-responsive element-binding protein

DRP1:

Dynamin-related protein 1

ERRα:

Estrogen-related receptor α

FBS:

Fetal bovine serum

FGF:

Fibroblast growth factor

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

GFP:

Green fluorescence protein

MAP2:

Microtubule-associated protein 2

Mfn2:

Mitofusin 2

mtDNA:

Mitochondrial DNA

mtROS:

Mitochondrial ROS

NRF1:

Nuclear respiratory factor 1

NSC:

Neural stem cell

PBS:

Phosphate-buffered saline

PGC-1α:

Peroxisome proliferator-activated receptor γ coactivator-1 α

PSEN1:

Presenilin 1

ROS:

Reactive oxygen species

Sirt3:

Sirtuin-3

SOD2:

Superoxide dismutase 2

Tfam:

Mitochondrial transcription factor A

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Acknowledgements

We are thankful to Dr. Jorge L. Ruas (Karolinska Institutet, Sweden) and Dr. David C. Chan (California Institute of Technology, USA) for kindly providing PGC-1α and Mfn2-Myc overexpression vectors, respectively. Finally, we thank all members of the laboratory, and especially Marta Fernandes, for insightful discussions.

Funding

This work was supported by UID/DTP/04138/2013, SFRH/BD/100674/2014, and SAICTPAC/0019/2015 from Fundação para a Ciência e Tecnologia, Portugal.

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Authors and Affiliations

  1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal

    Maria Filipe Ribeiro, Tânia Genebra, Cecília M. P. Rodrigues & Susana Solá

  2. CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Ana Cristina Rego

  3. FMUC-Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Ana Cristina Rego

Authors
  1. Maria Filipe Ribeiro
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  2. Tânia Genebra
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  3. Ana Cristina Rego
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  4. Cecília M. P. Rodrigues
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  5. Susana Solá
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Contributions

MFR, CMPR, and SS conceived and designed the experiments. MFR performed the experiments. TG contributed in establishing the in vitro model. MFR, SS, and CMPR analyzed and interpreted the data. ACR contributed with reagents. MFR wrote the manuscript. CMPR and SS critically reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Cecília M. P. Rodrigues or Susana Solá.

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The authors declare that they have no conflict of interest.

Electronic Supplementary Material

ESM 1

Tris buffer did not affect NSC viability. Mouse NSCs were treated with volumes of Tris buffer equivalent to 1.5, 5 or 10 μM Aβ in self-renewal conditions. After 24 h of Aβ treatment, cells were collected to assess viability and proliferation as described in Materials and Methods. Data represents mean values ± SEM for at least three independent experiments. (PNG 31 kb)

High resolution image (EPS 12342 kb)

ESM 2

Aβ peptide blocks NSC cycle re-enter. Mouse NSCs were treated with 10 μM Aβ in self-renewal conditions. After 48 h of treatment, cells were collected to assess proliferation by qRT-PCR of Ki67 expression. Data represents mean values ± SEM for at least three independent experiments. ***p < 0.001 compared to untreated cells. (PNG 20 kb)

High resolution image (EPS 8176 kb)

ESM 3

Neurogenesis inhibition by Aβ is not due to a double dosage the amyloid peptide. Five micromolar of Aβ was incubated at the same time of neuronal differentiation induction, for 48 h, with 24 h of 5 μM Aβ pre-incubation in self-renewal conditions. Samples were collected for flow cytometry analysis. Histograms of positive cells for nestin, βIII-tubulin, and MAP2 (top). Experimental scheme representing the protocol of treatment (bottom). (PNG 98 kb)

High resolution image (EPS 66696 kb)

ESM 4

Aβ inhibits gliogenic differentiation. Mouse NSCs were treated with Aβ (10 μM) for 48 h at the same time of glial differentiation induction. Samples were collected for flow cytometry analysis. Percentage of positive cells for nestin and GFAP were analyzed (top). Experimental scheme representing the protocol of treatment (bottom). Data represents mean values ± SEM for at least three independent experiments. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to untreated cells. (PNG 38 kb)

High resolution image (EPS 27759 kb)

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Ribeiro, M.F., Genebra, T., Rego, A.C. et al. Amyloid β Peptide Compromises Neural Stem Cell Fate by Irreversibly Disturbing Mitochondrial Oxidative State and Blocking Mitochondrial Biogenesis and Dynamics. Mol Neurobiol 56, 3922–3936 (2019). https://doi.org/10.1007/s12035-018-1342-z

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  • DOI: https://doi.org/10.1007/s12035-018-1342-z

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