Drug Development

Anxiety is a common symptom of Alzheimer's disease (AD). It has been recently established that anxiety is associated with AD pathology characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles. Our laboratory has demonstrated that acute administration of Aβ12-28P, a synthetic peptide with the potential to competitively inhibit toxic Aβ oligomers, resulted in improved cognitive function in old transgenic AD mice. However, whether inhibiting Aβ toxicity by Aβ12-28P also alleviates anxiety in AD mice remains unknown.

Middle-aged (12-15 months old) and old (18-24 months old) APP/PS1 dE9 mice were intraperitoneally injected with Aβ12-28P, while control mice received an equivalent volume of saline. Behavioral tests, including open field test and elevated plus maze, were conducted 2 hours post-injection to assess the acute effect of Aβ12-28P or saline on the anxiety of animals. We further performed in vivo fiber photometry to investigate anxiety-associated neural dynamics across multiple brain regions, such as ventral CA1 (vCA1), medial prefrontal cortex (mPFC), basal amygdala (BA), and lateral hypothalamic area (LHA). Adeno-associated virus expressing GCaMP8f was injected into target brain regions, above which an optic fiber was implanted. Four weeks later real-time calcium transients were recorded during anxiety tests.

In middle-aged AD mice, Aβ12-28P administration exerted acute anxiolytic effects in the open field test (n = 8 drugged versus 8 non-drugged, p < 0.05). Furthermore, anxiety was also significantly alleviated by Aβ12-28P in old AD mice in both the open field (n = 17 drugged versus 14 non-drugged, p < 0.0001) and elevated plus maze (n = 11 drugged versus 12 non-drugged, p < 0.05) tests. We further compared the neural activity patterns in brain regions, such as vCA1, mPFC, BA, and LHA, with or without Aβ12-28P treatment by fiber photometry. Our data suggested significant modification of anxiety-associated neural dynamics in these brain regions by Aβ12-28P administration.

These results suggest that Aβ12-28P has an acute anxiolytic effect in both middle-aged and old AD mice. Our finding opens the possibilities to apply the strategy of targeting Aβ pathology for alleviating neuropsychiatric AD symptoms, such as anxiety, and provide insights into a brain region-specific mechanism behind this therapeutic strategy.