Cited by 247Pluripotent Stem Cells ResearchAlzheimer's disease research and treatmentsNeurogenesis and neuroplasticity mechanisms

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Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients

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Mertens, Jerome, Herdy, Joseph R., Traxler, Larissa, Schafer, Simon T., Schlachetzki, Johannes C.M., Böhnke, Lena, Reid, Dylan A., Lee, Hyungjun, Zangwill, Dina, Fernandes, Diana P., Agarwal, Ravi K., Lucciola, Raffaella, Zhou-Yang, Lucia, Karbacher, Lukas, Edenhofer, Frank, Stern, Shani, Horvath, Steve, Paquola, Apua C.M., Glass, Christopher K., Yuan, Shauna H., Ku, Manching, Szücs, Attila, Goldstein, Lawrence S.B., Galasko, Douglas, Gage, Fred H.·2021·Cell Stem Cell

DOI 10.1016/j.stem.2021.04.004PMC PMC8423435

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Abstract

Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.

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TL;DR

Directly converted induced neurons (iNs) from Alzheimer’s disease patients retain age-equivalent neuronal identity and show a hypo-mature, de-differentiated state with loss of mature neuronal gene expression and functional deficits. This AD-related instability is age-dependent: rejuvenated iPSC-derived neurons from the same patients show no significant disease transcriptome signature.

Key findings

AD iNs had 778 highly significant DE genes (FDR < 0.01), while parental fibroblasts showed no significant AD-specific DE genes; AD iN transcriptomes overlapped with post-mortem AD brain and neuronal single-nucleus AD signatures.
Downregulated genes in AD iNs were enriched for mature neuronal categories including synaptic transmission, oxidative phosphorylation, neuronal action potential, ion transport, and mitochondria; AD iNs showed reduced dendritic complexity, fewer synapsin and synapsin/PSD-95 puncta, and reduced spontaneous Ca²⁺ event frequency.
Upregulated genes in AD iNs were enriched for cell cycle, stem/progenitor maintenance, stress, apoptosis, senescence, and cancer-related pathways; ATAC-seq showed on average 36% more open chromatin peaks that were 7% wider, with 7,188 differentially accessible peaks, 97% gained in AD.
Rejuvenated iPSC-derived neurons showed no significant DE genes between control and AD subjects; iN DNA methylation ages reflected donor adult/old ages, whereas iPSC derivatives reflected pre-natal ages, and AD iNs did not show accelerated epigenetic aging over controls.

Methods

Fibroblasts from 16 AD subjects (13 sporadic, 3 familial) and 19 age- and sex-matched non-demented controls were directly converted into iNs using Ngn2/Ascl1-based, small-molecule-enhanced conversion and PSA-NCAM FACS isolation.
Assays included whole-genome RNA-seq, ATAC-seq, DNA methylation EPIC arrays, immunofluorescence, ELISA for Aβ42/40, ROS measurement, live-cell Ca²⁺ imaging, and morphological reconstruction.
A subset (n = 20) was reprogrammed to iPSCs and converted to iPSC-iNs as rejuvenated isogenic controls; transcriptomes were compared with post-mortem bulk and single-nucleus AD data, BrainSpan fetal/adult brain samples, and published neuronal differentiation trajectories.

Limitations

Stated in the paper: fibroblasts carry skin-specific, age-related changes that might interfere with AD-related iN changes; some brain-specific changes might not be captured; Ngn2/Ascl1 overexpression might override endogenous differences; other iPSC differentiation models might recapitulate AD phenotypes more prominently; and the cohort might not fully represent all AD patients.
Evident from the text: the model is in vitro and fibroblast-derived, and although AD iNs showed cell cycle re-entry markers and increased DNA content above diploid, no completed neuronal DNA replication was detected, so conclusions about cell cycle re-entry rely on markers and aneuploidy rather than completed division.

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Crossref · 10.1016/j.stem.2021.04.004

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In the paper
“Similar to iNs, iPSC-iN cultures contained vGlut1+ and GABA+ neurons and expressed marker genes for both subtypes, and both showed the highest similarity to cortical excitatory neurons from single-cell RNA-seq (scRNA-seq) data (Figure 7D; Figure S5; Mathys et al., 2019).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Results > Isogenic iPSC-derived neurons show only very dampened AD transcriptome changes
What the sources say
- Not checked yetcites Mathys et al., 2019 source
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In the paper
“As shown previously, conversion of iPSCs to iPSC-iNs is highly efficient, as virtually all EGFP-positive iPSCs convert into neurons that also predominantly express NeuN and vGlut1 (Figures S5; Schafer et al., 2019).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Results > Isogenic iPSC-derived neurons show only very dampened AD transcriptome changes
What the sources say
- Not checked yetcites Schafer et al., 2019
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Consistently, aging genes in iNs previously identified by RNA-seq from a healthy aging cohort did not show extended changes in AD iNs, and plotting AD iN DE genes across healthy aging iNs did not indicate their regulation by age; rather, a slightly inverse trend was detected (Figure 7J; Figure S6; Mertens et al., 2015a).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Results > Directly converted iNs reflect an old and adult neuronal ontogenic identity, whereas iPSC-derived neurons represent rejuvenated and fetal-like states
What the sources say
- Not checked yetcites Mertens et al., 2015a
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In the paper
“However, familial AD is comparatively rare, and sporadic AD cases that develop without clear genetic etiology represent the vast majority of cases, wherein disease risk increases exponentially with age (Querfurth and LaFerla, 2010).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Introduction
What the sources say
- Not checked yetcites Querfurth and LaFerla, 2010 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In contrast, direct conversion of human fibroblasts into induced neurons (iNs) bypasses the embryo-like state and directly results in postmitotic neurons with mature marker expression and functionality (Liu et al., 2013; Pang et al., 2011).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Introduction
What the sources say
- Not checked yetcites Liu et al., 2013 source
- Not checked yetcites Pang et al., 2011
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It may state two separate claims as one.
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In the paper
“However, reprogramming into pluripotency leaves old, donor-derived iPSC-derived neurons with practically no traces of their donors’ ages, and iPSC-associated cellular rejuvenation represents a major challenge when attempting to model age-dependent diseases (Böhnke et al., 2018; Kang et al., 2016; Mertens et al., 2015a; Miller et al., 2013; Tang et al., 2017).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Introduction
What the sources say
- Not checked yetcites Böhnke et al., 2018
- Not checked yetcites Kang et al., 2016
- Not checked yetcites Mertens et al., 2015a
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, the AD iN-specific chromatin landscape changes accommodate a persistent lack of a differentiated identity and suggest that epigenetic changes might underlie the transcriptional and functional lack of the differentiated state in AD neurons.”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Results > Epigenetic landscape changes underlie hypo-mature neuronal state
Load-bearingStrength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: Stem and progenitor cells, as well as transformed cells, typically reflect a globally open chromatin state, whereas differentiated cells possess a more defined and closed chromatin landscape.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, AD iNs show signs of elevated ROS, DNA damage, and aneuploid DNA contents, which may trigger neuronal de-differentiation and lead to an aberrant hypo-mature cellular state that partially mirrors a stem/progenitor-associated transcriptional program and expression of non-neuronal proteins, including markers of cell cycle and non-neuronal energy metabolism.”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Results > AD patient iNs display markers of stress-related de-differentiation
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It may state two separate claims as one.
- Rests on an assumption: LDHA is inversely associated with mature neuronal identity.
None of the sources cited for this claim have been checked yet.
In the paper
“Erosion of epigenetic control and transcriptional drift and the incidence of malignant transformation are strongly associated with human aging (Veitia et al., 2017; Zheng et al., 2016a).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Results > Isogenic iPSC-derived neurons show only very dampened AD transcriptome changes
What the sources say
- Not checked yetcites Veitia et al., 2017
- Not checked yetcites Zheng et al., 2016a
Strength:boosted· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Neuronal de-differentiation, loss of mature neuronal fate, and markers that suggest a re-entry of neurons into the cell cycle are pathological hallmarks of AD (Arendt, 2012; Arendt et al., 2000; Busser et al., 1998; Currais et al., 2009; Herrup and Yang, 2007; McShea et al., 1999; Nagy et al., 1997; Yang et al., 2001).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Discussion
What the sources say
- Not checked yetcites Arendt, 2012
- Not checked yetcites Arendt et al., 2000
- Not checked yetcites Busser et al., 1998
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In the paper
“Outside of the nervous system, epigenetic erosion and loss of cell identity are established key features of aging (Ma et al., 2018; Teschendorff et al., 2013; Veitia et al., 2017; Wang et al., 2008; Zheng et al., 2016a).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Discussion
What the sources say
- Not checked yetcites Ma et al., 2018
- Not checked yetcites Teschendorff et al., 2013
- Not checked yetcites Veitia et al., 2017
Strength:boosted· not yet calibratedCausal:correlational· not yet calibrated
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Our data are consistent with the observation that oxidative stress and DNA damage can induce cell cycle re-entry markers of neurons (Walton et al., 2019; Yang et al., 2001), leading to neuronal hypo-maturity and functional defects (Kruman et al., 2004; Sharma et al., 2017), that might further lead to metabolic reprogramming, activation of cell death competence (Benn and Woolf, 2004; Kole et al., 2”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Discussion
What the sources say
- Not checked yetcites Walton et al., 2019
- Not checked yetcites Yang et al., 2001
- Not checked yetcites Kruman et al., 2004
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
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It may state two separate claims as one.
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In the paper
“Injury is a well-established trigger of cellular de-differentiation, and the changes we observed are likely a consequence of human neurons adhering to this principle (Gu et al., 2020; Jopling et al., 2010; Poplawski et al., 2020; Renthal et al., 2020; Tzahor and Poss, 2017; Wagner et al., 2017).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Discussion
What the sources say
- Not checked yetcites Gu et al., 2020
- Not checked yetcites Jopling et al., 2010 source
- Not checked yetcites Poplawski et al., 2020 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Collectively, for studying age-related vulnerability and mechanisms relevant to AD, iNs have advantages over iPSC models and thus complement isogenic iPSC strategies (van der Kant et al., 2019; Meyer et al., 2019; Woodruff et al., 2013).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Discussion
What the sources say
- Not checked yetcites van der Kant et al., 2019 source
- Not checked yetcites Meyer et al., 2019 source
- Not checked yetcites Woodruff et al., 2013 source
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In the paper
“Previous studies on Huntington’s disease have consistently detected signs of neuronal epigenetic instability (Ayata et al., 2018; von Schimmelmann et al., 2016).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > Discussion
What the sources say
- Not checked yetcites Ayata et al., 2018 source
- Not checked yetcites von Schimmelmann et al., 2016 source
Strength:boosted· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the ‘in vitro clock,’ also known as the ‘skin and blood clock,’ was used as it best predicts chronological ages of cell culture samples (Horvath et al., 2019).”
§ Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients > STAR★Methods > Method details
What the sources say
- Not checked yetcites Horvath et al., 2019
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
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48 of 48

The paper relies on this without support.
Aging is crucial for age-related neurodegenerative diseases to unfold.
“Because aging is likely crucial for age-related neurodegenerative diseases to unfold, we generated age-equivalent fibroblast-derived iNs from a cohort of primarily sporadic AD patients and cognitively normal controls.”
The paper relies on this without support.
Stem and progenitor cells, as well as transformed cells, typically reflect a globally open chromatin state, whereas differentiated cells possess a more defined and closed chromatin landscape.
“Stem and progenitor cells, as well as transformed cells, typically reflect a globally open chromatin state, whereas differentiated cells possess a more defined and closed chromatin landscape (Figure 6A).”
The paper relies on this without support.
LDHA is inversely associated with mature neuronal identity.
“We assessed lactate dehydrogenase A (LDHA), a canonical glycolysis gene that is inversely associated with mature neuronal identity and is downregulated during neuronal differentiation (Figure 5G).”
The paper relies on this without support.
Transcriptome similarity between cultured neurons and BrainSpan cortical samples reflects their ontogenic (developmental) identity.
“To classify the iNs and iPSC-iNs on an ontogenic identity scale, we compared our transcriptome data with samples from the entire range of human cortical brain development (Figure 7K).”

4 of 4

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Addgene identifiers conflict between resource sections
Minor
The key resources table assigns #127289 to the Ascl1 construct and #84777 to the EGFP construct. Materials availability instead assigns #127288 to Ascl1 and #127289 to EGFP.
Calcium-imaging cell counts exceed the stated sampling plan
Minor
The methods specify 10 donors, three fields per donor, and 10 cells per field, which gives 300 cells total, or 150 per group given the five donors per group in the caption. Figure 3 instead reports 160 control cells and 184 AD cells.
Mature-neuron results point to incompatible Figure 4 panels
Minor
The text cites Figures 4C and 4D for downregulated mature-neuronal gene sets and markers. The Figure 4 caption identifies those panels as upregulated KEGG pathways and dysregulated gene sets; Figure 3C and 3D are captioned as the mature-neuronal results.

3 of 3

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Authors: Mertens, J., Herdy, J. R., Traxler, L., Schafer, S. T., Schlachetzki, J. C. M., Böhnke, L., Reid, D. A., Lee, H., Zangwill, D., Fernandes, D. P., Agarwal, R. K., Lucciola, R., Zhou-Yang, L., Karbacher, L., Edenhofer, F., Stern, S., Horvath, S., Paquola, A. C. M., Glass, C. K., Yuan, S. H., Ku, M., Szücs, A., Goldstein, L. S. B., Galasko, D., & Gage, F. H.
Affiliations: Salk Institute for Biological Studies (US)
University of California San Diego (US)
Universität Innsbruck (AT)
University of California, Los Angeles (US)
University of Minnesota (US)
University of Freiburg (DE)
Corresponding author: Gage, Fred H.
ORCID: Herdy, Joseph R.
Traxler, Larissa
Schafer, Simon T.
Schlachetzki, Johannes C.M.
Böhnke, Lena
Reid, Dylan A.
Lee, Hyungjun
Zhou-Yang, Lucia
Karbacher, Lukas
Edenhofer, Frank
Stern, Shani
Horvath, Steve
Glass, Christopher K.
Yuan, Shauna H.
Ku, Manching
Goldstein, Lawrence S.B.
Galasko, Douglas
Gage, Fred H.
Venue: Cell Stem Cell
Publisher: Elsevier BV
Published: 2021-09
Volume: 28
Issue: 9
Pages: 1533-1548.e6
ISSN: 1875-9777 (ISSN-L)
1934-5909
DOI: 10.1016/j.stem.2021.04.004
PMC: PMC8423435
OpenAlex: W3157334032
Semantic Scholar: 8048718b1b52a70eeaec2916188b07119caa46f5
Cited by: 240
References: 110
Citations by year: 2026: 34 · 2025: 45 · 2024: 54 · 2023: 54 · 2022: 42 · 2021: 11
FWCI: 13.19
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Cell stem cell (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
ELTE Digital Institutional Repository (EDIT) (Eötvös Loránd University) (submittedVersion, other-oa)
Funders: Leona M. and Harry B. Helmsley Charitable Trust
University of California, San Diego
Marshallplan-Jubiläumsstiftung
Deutsche Forschungsgemeinschaft
Austrian Science Fund (ANN-135291)
BrightFocus Foundation
Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie
Alzheimer's Disease Research Center, Emory University
Alzheimer Nederland
European Commission (ERC-STG-2019-852086, H2020-MSCA-IF-2017-797205)
Alzheimer's Association
Deutscher Akademischer Austauschdienst
American Heart Association
G. Harold and Leila Y. Mathers Charitable Foundation
Allen Foundation (19PABH134610000)
National Institutes of Health (AG056306, AG056511, AG057706, AG062429)
European Research Council
National Institute on Aging (K99-AG056679)
Horizon 2020 Marie Skłodowska-Curie Actions
EU Joint Programme – Neurodegenerative Disease Research
California Institute for Regenerative Medicine (RT2-01927)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: Alzheimer's disease, induced neurons, neuronal identity, neuronal maturation, fibroblast-to-neuron conversion, iPSC-derived neurons, epigenetic clocks, dedifferentiation, neuronal transcriptome
MeSH terms: Aged, Aging, Alzheimer Disease, Fibroblasts, Humans, Neurons, Induced Pluripotent Stem Cells

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Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients

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