Unravelling the complex interplay of Aβ, inflammation and synaptic defects in mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, characterized by memory loss and cognitive and behavior changes. AD pathology consists of an increased formation of amyloid plaques, tau-fibrils, inflammation and neurodegeneration in the brain. Amyloidosis and inflammation, both early events, have gained interest as potential causes of AD, which puts the focus of many studies on these events. Soluble amyloid beta oligomers (sAβ) and inflammation lead to synaptic defects at an early stage, affecting synaptic transmission mechanisms (e.g. long term potentiation) necessary for learning and memory. This eventually results in cognitive defects arising in late stage AD. However, treatment studies targeting amyloidosis and inflammation have led to inconsistent results. A plausible explanation is that many studies have been focusing on amyloid plaques, while sAβ, occurring even earlier, is more likely to be the culprit behind the AD symptoms. Furthermore, amyloidosis and inflammation seem to be closely related, since tackling inflammation pre-and post-plaque stage show different effects on pathology i.e. amelioration and aggravation respectively. The synaptic defects caused by sAβ and inflammation may result in altered brain functional connectivity (FC), which can be measured in vivo using resting state functional MRI (rsfMRI) and which is defined as the temporal correlation of the low frequency fluctuations (LFF) in the Blood-Oxygenation-Level-Dependent (BOLD) signal of spatially distinct areas.Our hypothesis is that amyloidosis, inflammation and synaptic defects are closely related and influence each other starting from early stages in AD. They represent interesting targets for drug development but much is unknown about these events. We believe that unravelling this complex interplay in mouse models will be useful for studies in animals and AD patients. Furthermore, we believe that the synaptic defects in AD could be reflected as alterations in FC. This could mean that rsfMRI may represent an in vivo method to follow up synaptic integrity in different stages of disease and to monitor the effect of manipulations.

Keywords:NEURODEGENERATIVE BRAIN DISEASES, ALZHEIMER'S DISEASE, INFLAMMATION, MRI (FUNCTIONAL)

Disciplines:Multimedia processing, Biological system engineering, Signal processing, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing