Grant: Project Grant

The onset of Alzheimer's disease (AD) is poorly understood. AD pathology develops silently for decades before its clinical presentation. During such phase, there should be a progressive accumulation of toxic proteins (amyloid-beta and tau) in the brain. We also recently characterized an early, disease-aggravating, pro-inflammatory process using genetically modified (GM) animal models of the disease. The Locus Coeruleus (LC) is a structure located deep in the brain which releases noradrenaline (NA), a neurotransmitter with anti-inflammatory properties. In AD, LC neurons degenerate particularly early-on due to tau pathology. Little is known about the downstream consequences of LC degeneration on the AD evolution. We aim at elucidating how LC pathology affects the earliest AD brain inflammation. We postulate that LC degeneration exacerbates such early inflammatory process which in turn potentiates and aggravates the amyloid pathology. To address this, we will use GM rats that replicate the progressive amyloid pathology observed in humans and also display pre- and post-plaque neuroinflammation. We will manipulate the LC of these GM rats to create an early dysfunction (by either triggering tau accumulation or lesioning LC nerve cells) or, in opposition, stimulate the LC to release NA. This will allow us to assess the direct impact of an inactivation or activation of the LC, respectively, on inflammation and amyloid pathology. These investigations will contribute significantly to the understanding of the early disease-aggravating pathological events occurring at pre-diagnostic stages of AD. The findings should offer new clues to halt the progression of AD before irreversible brain damage and thus may provide new targets for development of novel early therapeutic interventions.