CHEMOGENETIC STIMULATION OF THE LOCUS COERULEUS INCREASES RESILIENCE TO PATHOLOGY IN A TRANSGENIC RAT MODEL OF ALZHEIMER'S DISEASE

There are currently no disease-modifying treatments for Alzheimer’s disease (AD), making it critical to identify strategies that delay symptom onset and slow disease progression. Therefore, we aim to understand the biological mechanisms underlying cognitive resilience (CR) in the context of AD. In particular, we have focused on the locus coeruleus (LC) as a potential modulator of CR. The LC is the major source of noradrenaline (NA) in the brain, and its widespread projections play a central role in regulating cognitive function, brain connectivity, and neuroinflammation. Importantly, extensive LC degeneration strongly correlates with pathological burden and symptom severity in AD, making it an attractive therapeutic target. Male and female wild-type and TgF344-AD rats underwent bilateral stereotaxic injections of excitatory DREADDs into the LC to selectively increase neuronal firing and consequently NA release. After a four-week period for optimal DREADD expression, animals received either a DREADD agonist or vehicle. Subsequently, MRI scans were acquired to assess LC-driven functional network-level effects of noradrenergic modulation. Behavioural testing was then conducted to assess memory, anxiety, and anhedonia. Vehicle-treated TgF344-AD rats exhibited anhedonia-like behaviour and cognitive impairments. In contrast, LC-stimulated rats showed increased reward responsiveness and restored memory performance. Notably, memory improvements were more pronounced in male TgF344-AD rats, consistent with their greater baseline impairments. In parallel, MRI analyses supported LC-driven modulation of functional brain connectivity. These findings demonstrate that LC activation ameliorates cognitive and emotional deficits in this AD model and support the LC–NA system as a promising therapeutic target to enhance CR.