Neuroinflammation and amyloid-β in early Alzheimer’s disease. Insight into the earliest events using mouse models

Alzheimer’s disease (AD) is the leading cause of dementia and most common neurodegenerative disease worldwide, but there currently exists no effective treatment that can stop nor slow the progression of the disease. The current dogma in the field postulates that the appearance of extracellular amyloid-beta (Aβ) plaques, a histopathological hallmark of the disease, is the trigger for downstream, detrimental events, including neuronal loss, extensive neuroinflammation and cognitive decline. However, increasing evidence suggests that neuroinflammatory alterations and synaptic and neuronal dysfunction occur already before plaque deposition, which we have also noted in previous work done by our groups. In addition, we have found that Aβ aggregates intracellularly, especially within neurons, before plaque appearance and that this has the ability to impair synaptic function. Therefore, we wonder whether there is an interplay between the neuroinflammatory system, neuronal and synaptic alterations, and intracellular Aβ in the earliest stages of the disease. To address this, we utilize mouse-based models in vivo, primarily the 5xFAD transgenic mouse model, and in vitro neuronal culture models. In the scientific papers included in this thesis work, we explore aspects related to mechanisms and modulations related to early AD. This includes looking at the prion-like spread and properties of intracellular Aβ, identifying sex-specific effects of early-life stress on inflammatory systems as well as neurons and Aβ, and investigating the interaction between neuroinflammatory cells and early aggregated Aβ. Taken together, we have worked to elucidate the earliest events in the disease, including factors that can modulate pathogenesis and the underlying mechanisms. By fostering a greater understanding of AD, we attempt to aid efforts towards the development of an effective disease-modifying treatment.