Seizures worsen tau spread preferentially in hyperactive neurons in a murine tauopathy model
Year: 2025
Type: article
Abstract: BACKGROUND: The spread of pathological tau through communicating neurons is central to neurodegeneration in Alzheimer's disease (AD). In addition, seizures are a common occurrence in AD and exacerbate both cognitive and pathological disease outcomes. We have recently demonstrated increased seizure susceptibility, and enhanced seizure-induced tau spread in a β-amyloid mouse model. We next sought to determine whether there are similar seizure susceptibility phenotypes and brain-wide effects of seizure induction on tau spread in a tauopathy mouse model. Given the role of tau in network excitability, we hypothesized that T40PL-GFP mice, harboring a GFP tagged pathogenic MAPT mutation (P301L), would show increased seizure susceptibility, and that seizures would worsen tau spread in these mice. METHOD: To investigate seizure-tau interactions, we crossed the T40PL-GFP mouse model with targeted recombination in active populations mice (TRAP; T40/WT-TRAP) to permanently label seizure activated neurons with tdTomato. To induce tau spread, we unilaterally injected human AD brain derived tau lysate (AD-tau) into the right hippocampus and cortex at three months of age. Seizures were induced with pentylenetetrazol (PTZ) kindling (or control, saline protocol) 2-3 weeks following AD-tau injection and seizure-activated neurons were labelled with tdTomato on the final PTZ administration via 4-hydroxytamoxifen administration. All mice were euthanized three months following AD-tau seeding, and intact T40-TRAP brains underwent clearing, immunolabeling for NeuN, and light sheet microscopy to image tau-GFP, tdTomato, and NeuN. Whole-brain datasets were registered to the Allen Brain Atlas and tdTomato+ and tdTomato- (NeuN+) somatic tau-GFP were mapped. RESULT: We found that T40PL-GFP mice had increased seizure susceptibility compared to WT mice (n =9-11, p <0.05). We also found significantly increased tau-GFP in seizure activated tdTomato+ neurons compared to neurons in saline treated mice in the ipsilateral and contralateral (to injection site) striatum, ipsilateral perirhinal and orbital areas, and contralateral nucleus raphe (n =4-5, p <0.05). tdTomato+ neurons also had elevated tau-GFP compared to the surrounding tdTomato- neurons in the ipsilateral striatum and perirhinal area (n =4-5, p <0.05). CONCLUSION: Together, these results demonstrate a bidirectional relationship between neuronal hyperactivity and tau pathology, and suggest seizures and seizure activated neurons as targets to slow progression of tau pathology.
Source: Alzheimer s & Dementia
Institution: University of Pennsylvania
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
OpenAlex ID: W7117018063
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