Multi-modal comparative phenotyping of knock-in mouse models of frontotemporal dementia/amyotrophic lateral sclerosis

Topic: Brain proteins, microglia and lab models

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive adult-onset neurodegenerative diseases with overlapping pathological and genetic origins. They are caused by multiple underlying mechanisms leading to a common collection of clinical features that occur in a spectrum. Here, we report side-by-side longitudinal behavioural, cognitive and sensory phenotyping of two mouse models of ALS/FTD, to determine which aspects of the disease they recapitulate. We used knock-in models, in which the endogenous mouse orthologues of the C9orf72 and TARDBP (encoding TDP-43) genes have been altered to model specific molecular aspects of ALS/FTD. We found that the C9orf72GR400/+ model exhibits age-related deficit in short-term memory and that parental genotype affects exploration activity in offspring. In the TardbpQ331K/Q331K model, we found age-related changes in weight, fat mass, locomotion and marble burying. In both models, we found no evidence of deficits in vision or olfactory habituation-dishabituation. These data provide new insight into genotype-phenotype relationships in these ALS/FTD mice, which can be used to inform model choice and experimental design in future research studies.

@article{boyanova2025-40856010,
  author  = {Boyanova, Sevda Tomova and Banks, Gareth T. and Lipina, Tatiana V. and Bains, Rasneer Sonia and Forrest, Hamish and Stewart, Michelle E. and Carcolé, Mireia and Milioto, Carmelo and others},
  title   = {{Multi-modal comparative phenotyping of knock-in mouse models of frontotemporal dementia/amyotrophic lateral sclerosis}},
  journal = {Disease Models \& Mechanisms},
  year    = {2025},
  doi     = {10.1242/dmm.052324},
  pmid    = {40856010},
  url     = {https://doi.org/10.1242/dmm.052324}
}

Key findings

• We found that the C9orf72GR400/+ model exhibits age-related deficit in short-term memory and that parental genotype affects exploration activity in offspring.
• In the TardbpQ331K/Q331K model, we found age-related changes in weight, fat mass, locomotion and marble burying.
• In both models, we found no evidence of deficits in vision or olfactory habituation-dishabituation.

Why it matters

This study compared behaviour, cognition and sensory function in two knock-in mouse models of frontotemporal dementia and amyotrophic lateral sclerosis, finding age-related short-term memory deficits in one model and weight, fat mass, locomotion and marble burying changes in the other. These are animal model characterisation findings intended to inform future research design and do not test any treatment, cure or prevention for Alzheimer's disease.

Study details

• Study designlongitudinal study
• Evidence strengthModerate

Read the original

• DOI: 10.1242/dmm.052324
• PubMed: 40856010
• Original source →
• Free full text: Disease Models & Mechanisms →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 13.

• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD Neuron · 2011-09-21 · usefulness score 63/100 · Lewy body dementia
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron · 2011-09-21 · usefulness score 62/100 · Lewy body dementia
• C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins Science (New York, N.Y.) · 2014-08-07 · usefulness score 58/100 · Lewy body dementia
• TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD Nature neuroscience · 2018-03-19 · usefulness score 56/100 · Brain tissue and pathology
• TDP-43 Pathology in Alzheimer's Disease Molecular neurodegeneration · 2021-12-20 · usefulness score 56/100 · Lewy body dementia
• TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration Annals of neurology · 2009-04-01 · usefulness score 54/100 · Brain tissue and pathology
• Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs Neuron · 2016-04-21 · usefulness score 54/100 · Lewy body dementia
• Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria Amyotrophic lateral sclerosis & frontotemporal degeneration · 2017-01-05 · usefulness score 54/100 · Getting a diagnosis
• Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death Neuron · 2014-12-01 · usefulness score 52/100 · Lewy body dementia
• C9orf72-mediated ALS and FTD: multiple pathways to disease Nature reviews. Neurology · 2018-09-01 · usefulness score 52/100 · Lewy body dementia

Related studies in Lewy body dementia

• A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study The Lancet. Neurology · 2011-12-07 · usefulness score 61/100
• TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia The Lancet. Neurology · 2010-10-01 · usefulness score 57/100
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100
• Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Annals of neurology · 2008-07-01 · usefulness score 54/100
• TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia Journal of Clinical Investigation · 2025-06-01 · usefulness score 51/100
• Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects Science Advances · 2025-04-16 · usefulness score 44/100

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