Evidence map›Paper›PMID 40390134›Full record

ArticleActa neuropathologica communications2025

hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation.

Ian Weidling, Christina N Preiss, Sarah E Chancellor, Gyan Srivastava, Lauren Gibilisco, Gen Lin, Melanie Shackett Brennan, Janice Lee, Lindsay M Roth, Olga Morozova and 21 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Article
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

31 authors.

Ian Weidling *AbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Christina N PreissAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Sarah E ChancellorAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Gyan Srivastava *AbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Lauren GibiliscoAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Gen LinAbbVie Pte Ltd, 9 North Buona Vista Drive #19-01, Singapore, 138588, Singapore.
Melanie Shackett BrennanAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Janice LeeAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Lindsay M RothAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Olga MorozovaAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Kyong Nyon NamAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Nehal R PatelAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Qing LiuAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
J K Thomas *AbbVie, Chicago, USA.
Peter ReinhardtAbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Ruven WilkensAbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Dagmar E EhrnhoeferAbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Andreas StriebingerAbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Stefan BarghornAbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Christina XanthopoulosAbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Marie-Theres Weil *AbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Sandra BiesingerAbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Miroslav CikAbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Nandini RomanulAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Kiran YanamandraAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Alessandra M WelkerAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Jessica WuAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Laura GaspariniAbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
Jan StöhrAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Xavier LangloisAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
Justine D ManosAbbVie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA, 02139, USA. justine.manos@abbvie.com.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Alzheimer's disease (AD) is characterized by the accumulation and spread of Tau intraneuronal inclusions throughout most of the telencephalon, leaving hindbrain regions like the cerebellum and spinal cord largely spared. These neuropathological observations, along with the identification of specific vulnerable sub-populations from AD brain-derived single nuclei transcriptomics, suggest that a subset of brain regions and neuronal subtypes possess a selective vulnerability to Tau pathology. Given the inability to culture neurons from patient brains, a disease-relevant in vitro model which recapitulates these features would serve as a critical tool to validate modulators of vulnerability and resilience. Using our recently established platform for inducing endogenous Tau aggregation in human induced pluripotent stem cell (hiPSC)-derived cortical excitatory neurons via application of AD brain-derived exogenous Tau aggregates, we explored whether Tau aggregates preferentially induce aggregation in specific neuronal subtypes. We compared Tau seeding in hiPSC-derived neuron subtypes representing regional identities across the forebrain, midbrain, and hindbrain. Higher susceptibility (i.e. more Tau aggregation) was consistently observed among cortical neuron subtypes, with CTIP2-positive, somatostatin (SST)-positive cortical inhibitory neurons showing the greatest aggregation levels across hiPSC lines from multiple donors. hiPSC-neurons also delineated between the disease-specific vulnerabilities of different protein aggregates, as α-synuclein preformed fibrils showed an increased propensity to induce aggregates in midbrain dopaminergic (mDA)-like neurons, mimicking Parkinson's disease (PD)-specific susceptibility. Aggregate uptake and degradation rates were insufficient to explain differential susceptibility. The absence of a consistent transcriptional response following aggregate seeding further indicated that intrinsic neuronal subtype-specific properties could drive susceptibility. The present data provides evidence that hiPSC-neurons exhibit features of selective neuronal vulnerability which manifest in a cell autonomous manner, suggesting that mining intrinsic (or basal) transcriptomic signatures of more vulnerable compared to more resilient hiPSC-neurons could uncover the molecular underpinnings of differential susceptibility to protein aggregation found in a variety of neurodegenerative diseases.

Indexed as

Alzheimer DiseaseInduced Pluripotent Stem CellsNeurodegenerative DiseasesNeuronsProtein Aggregation, Pathologicaltau ProteinsHumansMAPT protein, humantau ProteinsAlzheimer’s diseasehiPSC-derived neuronsParkinson’s diseaseSelective vulnerabilityTau

Identifiers

PMID40390134
PMCPMC12087151

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.