TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice

Topic: Brain proteins, microglia and lab models

TAR DNA-binding protein 43 (TDP-43) pathology is linked to the neurodegenerative disorders amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington disease (HD). Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalamic pathology. Inclusions with TDP-43 are present in the hypothalamus in clinical ALS, as well as selective loss of hypothalamic neurons expressing the metabolism and emotion regulating neuropeptides hypocretin (orexin), melanin-concentrating hormone (MCH) and oxytocin. We aimed to investigate whether there is a casual link between the effects of TDP-43 in the hypothalamus and the development of neuropathology, as well as changes in metabolism and behavior. We generated an adeno-associated viral (AAV) vector expressing human TDP-43 under the neuronal-specific synapsin promoter, which was injected bilaterally into the hypothalamus of wild-type FVB/N mice. TDP-43 overexpression resulted in hypothalamic pathology in a dose-dependent fashion replicating clinical pathology with hypothalamic atrophy and loss of hypocretin-, MCH- and oxytocin-expressing neurons. Nuclear and cytoplasmic inclusions of TDP-43 were found in the hypothalamus. Mice overexpressing TDP-43 in the hypothalamus developed metabolic dysregulation with hyperglycaemia independent of food intake. Additionally, mice overexpressing TDP-43 in the hypothalamus exhibited reduced motor activity and nesting ability, suggesting the development of an apathy-like phenotype. Taken together, AAV-vector mediated TDP-43 overexpression in the hypothalamus leads to neuropathology with the development of metabolic dysfunction and apathy-like behavior. These results indicate that TDP-43 can exert direct pathological effects in the hypothalamus, which may contribute to the development of the non-motor phenotype in TDP-43 proteinopathies.

@article{bergh2025-40426231,
  author  = {Bergh, Sofia and Casadei, Nicolas and Gabery, Sanaz and Simonsson, Oskar and Duarte, João M. N. and Kirik, Deniz and Nguyen, Huu Phuc and Petersén, Åsa},
  title   = {{TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice}},
  journal = {Acta Neuropathologica Communications},
  year    = {2025},
  doi     = {10.1186/s40478-025-02018-8},
  pmid    = {40426231},
  url     = {https://doi.org/10.1186/s40478-025-02018-8}
}

Key findings

• Taken together, AAV-vector mediated TDP-43 overexpression in the hypothalamus leads to neuropathology with the development of metabolic dysfunction and apathy-like behavior.
• These results indicate that TDP-43 can exert direct pathological effects in the hypothalamus, which may contribute to the development of the non-motor phenotype in TDP-43 proteinopathies.

Why it matters

In mice, overexpressing TDP-43 in the hypothalamus caused hypothalamic atrophy, loss of specific neuropeptide-producing neurons, TDP-43 inclusions, high blood sugar independent of food intake, and apathy-like behavior. The authors conclude TDP-43 can have direct pathological effects in the hypothalamus that may contribute to non-motor symptoms in TDP-43 proteinopathies.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/s40478-025-02018-8
• PubMed: 40426231
• Original source →
• Free full text: Acta Neuropathologica Communications →

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

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