Studying the interaction between amyloid pathology, synaptic deficits and functional connectivity in mouse models of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common form of dementia, with a high prevalence in the elderly population. Symptoms include cognitive impairments and behavioural changes. AD pathology is characterized by the increased formation of (in)soluble forms of amyloid beta (Aβ), tau-fibrils and neurodegeneration. Currently, there are only symptomatic treatments available that can delay the onset of symptoms but do not cure the disease. Amyloid pathology and inflammatory responses, which occur at an early stage of disease, have been implied as possible driving forces behind AD. However, until now the exact cause of AD is still unknown. This emphasizes the importance of studying early stage pathological features of AD, to gain a better insight into mechanisms that lie at the basis of this disease. A better understanding of these early events will help to provide targets for the development of treatments that delay the symptoms for a longer period of time or even reverse them.

One of the earliest occurring pathological changes in AD are synaptic deficits, which eventually lead to learning and memory dysfunctions. The synaptic dysfunctions in AD are possibly a consequence of the soluble form of amyloid (sAβ), which exerts toxic effects at the level of the synapses. Additionally, sAβ induces inflammatory responses which might also affect synaptic function. These early pathological events will lead to functional changes in the brain before the appearance of any AD-related structural alterations such as brain atrophy. An example of such functional changes is altered functional connectivity (FC) in the brain, which can be measured, among others, using resting state functional magnetic resonance imaging (rsfMRI). 

Brain FC has been investigated extensively in AD patients, however, much remains unclear concerning the cause of the observed FC deficits in AD patients. Some studies have suggested a link between amyloid pathology and altered FC, but it is not straightforward to perform correlative studies in patients, who show several aspects of AD pathology i.e. amyloid pathology, tau-pathology, neuron loss etc. The advantage of using mouse models is that a specific aspect can be evaluated without the confounding effects of other pathological features. RsfMRI is a non-invasive technique and thus appropriate for longitudinal observational/treatment studies in animal models and translation to the clinic. We hypothesize that defects in synaptic transmission will affect FC in the brain.

In the current project we will focus on synaptic transmission deficits by first demonstrating that pharmacological modulation of synaptic transmission can be detected using functional MRI in healthy control animals. Next we will study the link between synaptic transmission defects, soluble amyloid and inflammation in a mouse model of amyloidosis using rsfMRI and histological validation. Finally, we will modulate amyloidosis and inflammation and evaluate the effects on pathology using rsfMRI and histology. Behaviour analyses will be performed to investigate the cognitive expression of our rsfMRI read-out. Our goal is to obtain a better understanding of the early events in AD, which will be beneficial in the context of treatment development.