Aging Frontotemporal Dementia Mouse Model Links Lysosomal Dysfunction to Synaptic Impairment

In a progranulin (Grn) knockout mouse model of frontotemporal dementia, aging is associated with behavioral alterations, lysosomal dysfunction, region-specific inflammation, and glutamatergic synaptic impairments. Researchers evaluating the model identified progranulin-related lysosomal dysfunction as a contributing factor to circuit disruption and behavioral deficits, pointing to a need for combinatorial therapeutic strategies that extend beyond progranulin replacement.

Progranulin-related frontotemporal dementia (GRN-FTD) is an inherited neurodegenerative disorder caused by progranulin (PGRN) deficiency. While progranulin functions are well characterized and several therapeutic strategies aiming to restore its levels are currently under evaluation, the mechanisms linking progranulin loss to neurodegeneration remain unclear.

Exploiting the Grn knockout mouse model, researchers investigated the impact of progranulin deficiency on behavior longitudinally across four time points: 4, 6, 9, and 12 months. Grn-mutant mice displayed genotype-specific, age-dependent impairments in pheromone perception, memory deficits, and increased aggression over time.

At 12 months of age, the final time point assessed in the study, the investigators examined glucocerebrosidase (GCase) activity, consequent glucosylsphingosine (GS) accumulation, neuroinflammation, and molecular and morphological alterations at glutamatergic synapses. Reduced GCase activity and GS accumulation confirmed lysosomal dysfunction in the mutant mice.

The confirmed lysosomal dysfunction was associated with brain-region-specific alterations in AMPA-type and NMDA-type glutamate receptor levels. In addition, morphological analysis revealed reduced dendritic spine density, an alteration observed specifically in Grn+/− mice.

These findings identify progranulin-related lysosomal dysfunction as a contributing factor to circuit disruption and behavioral deficits in the mouse model. Based on these observations, the authors highlight the need for combinatorial therapeutic strategies going beyond progranulin replacement alone.

Subject of Research: Lysosomal and synaptic pathology in progranulin-deficient frontotemporal dementia mouse models

Article Title: Aging is associated with behavioral alterations, lysosomal dysfunction, region-specific inflammation, and glutamatergic synaptic impairments in a Grn knockout mouse model of frontotemporal dementia

Article References: Bertasini, C., Italia, M., Tavakolian Haghighi, S., Salzano, S., Sorio, D., Murari, M., Gottardo, R., Galasso, M., Scupoli, M. T., Castagna, A., Cané, S., Wahlberg, L. U., Gardoni, F., & Paolone, G. (2026). Aging is associated with behavioral alterations, lysosomal dysfunction, region-specific inflammation, and glutamatergic synaptic impairments in a Grn knockout mouse model of frontotemporal dementia. Acta Neuropathologica Communications. https://doi.org/10.1186/s40478-026-02418-4

Image Credits: AI Generated

DOI: 10.1186/s40478-026-02418-4

Keywords: Frontotemporal dementia, Progranulin, Grn knockout mice, Lysosomal dysfunction, Glutamate receptors, Neuroinflammation, Synaptic plasticity, Neurodegeneration, Aging, associated, behavioral, alterations