Propagation of gut-injected AAV2/1-Htt171-82Q to the brain induces Huntington's disease-like pathology

Huntington's disease (HD) is a progressive neurodegenerative disorder that leads to thbe production of pathogenic mutant huntingtin (mHtt) protein and is characterized by motor and psychiatric symptoms. While HD has classically been studied as a brain-centered condition, emerging research indicates that the gut-brain axis may play a role in disease initiation and progression. However, direct experimental evidence demonstrating a peripheral-to-central route for mHtt propagation remains limited and unclear. Here, we tested whether mHtt expressed in the gastrointestinal tract could migrate to the brain via the vagus nerve and result in HD-associated motor and psychiatric symptoms. Rats received injections of an adeno-associated virus 2/1 (AAV2/1) vector encoding a pathogenic huntingtin fragment (Htt171-82Q) into the pyloric stomach and duodenum. Rats were assigned to groups with either intact or surgically transected vagus nerves and injected with either mutant or control vectors. In animals with intact vagus nerves, vector-derived mHtt signal became progressively detectable in brain regions including the medulla oblongata, substantia nigra, hypothalamus, striatum, hippocampus, and cortex. This was associated with mutant protein aggregation, neuroinflammation, reduced neuronal integrity, and impairments in motor as well as exploratory behavior. Electrophysiological recordings also revealed dysregulated neural firing activity in the striatum and cortex. In fine, these findings strongly support a vagus-dependent gut-to-brain accumulation of vector-derived mHtt signal, associated with widespread neuropathology and behavioral deficits. This model provides a controlled experimental framework for studying vagus-dependent gut to brain accumulation of vector-derived mHtt signal and its associated neuropathological and behavioral consequences.