DEVELOPMENT OF AN <EM >IN-VIVO</EM> MODEL OF TAUOPATHY THROUGH INTRA-HIPPOCAMPAL INJECTION OF HUMAN TAU PRE-FORMED FIBRILS INTO THE BRAINS OF AGED MICE

Accumulation of abnormal tau protein in neurons and glial cells is a defining feature of Alzheimer’s disease (AD) and other tauopathy-related neurodegenerative disorders. Hyperphosphorylated tau (p-Tau) forms insoluble aggregates and neurofibrillary tangles that disrupt neuronal function, drive synaptic loss, and ultimately lead to neurodegeneration and cognitive decline. Aging, the strongest risk factor for AD, creates a brain environment increasingly vulnerable to tau misfolding, impaired proteostasis, and heightened neuroinflammation. To model these age-dependent mechanisms in a translationally relevant context, we developed an in vivo tauopathy model using intra-hippocampal injection of human tau pre-formed fibrils (PFFs) in aged mice.
Eighteen-month-old male C57Bl/6J mice received bilateral intra-hippocampal injections of human Tau-441 PFFs and were evaluated for up to 12 weeks post-injection. Cognitive performance was assessed using the Y-maze and novel object recognition tests. Neurodegeneration (NeuN), p-Tau accumulation (AT100), and microglial activation (Iba1) were quantified using immunohistochemistry.
Tau PFF-injected aged mice displayed significant impairments in short-term spatial and object recognition memory compared with sham-treated controls. This cognitive decline was accompanied by increased neurodegeneration, robust neuronal p-Tau accumulation, and elevated neuroinflammation.
This aged in vivo tauopathy model reproduces key behavioral and histopathological features of AD following a single tau insult. This model complements our established amyloid-β oligomer–based model, enabling investigation of two converging yet mechanistically distinct drivers of AD pathology. Together, these aging-based models support evaluation of anti-tau, anti-amyloid, and aging-targeted therapeutic strategies, providing a versatile and translational platform for preclinical drug development.