Studying the interaction between amyloid pathology, synaptic deficits and functional connectivitty in mouse models of Alzheimer's disease

Date: 4 December 2017

Venue: UAntwerp, Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken)

Time: 5:00 PM - 7:00 PM

PhD candidate: Disha Shah

Principal investigator: Annemie Van der Linden, Marleen Verhoye, Rudi D'Hooge

Short description: PhD defence Disha Shah - Department of Biomedical Sciences



Abstract

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by cognitive and behavioural impairments. AD pathology includes increased formation and aggregation of pathological amyloid-beta, tau-fibrils and neurodegeneration. Currently, there are only symptomatic treatments available which restore the neurotransmitter balance that is perturbed in the AD brain and which can at best delay the progression of symptoms.

Efficient treatment development would require knowledge on the mechanisms involved in the initial phases of AD. According to the amyloid cascade hypothesis, amyloid pathology, which occurs at an early stage, is the driving force behind AD.  Soluble or pre-plaque stage amyloid-beta is synaptotoxic and leads to functional alterations of neuronal circuits. Thus, tools that allow detecting these functional changes non-invasively would be extremely useful to study early stages of AD. Resting-state functional Magnetic-Resonance-Imaging (rsfMRI) enables investigating neuronal circuits by assessing functional connectivity (FC), i.e. interregional correlation of neuronal activity patterns. The synaptotoxicity of pre-plaque amyloid-beta affects communication within and between neuronal circuits, and thus possibly FC.

In part 1 of this thesis we aimed to validate rsfMRI as a tool to detect synaptic changes using pharmacological and behavioural modulations in the mouse brain. We showed that pharmacological modulations of cholinergic and serotonergic neurotransmitter systems led to region-specific FC alterations. Behavioural modulations included firstly visual stimulation, which resulted in alterations of FC patterns in brain regions involved in stimulus processing. Secondly, we demonstrated that spatial learning increased functional connections which are important for spatial memory and processing. Thus, these studies established the use of rsfMRI to detect synaptic transmission changes and the brain’s remarkable plasticity elicited by modulations of synaptic activity.

In part 2 we aimed at assessing the use of rsfMRI in mouse models of amyloid pathology. An interesting pattern of spatiotemporal FC alterations was observed i.e. early (pre-plaque) hypersynchrony of FC in hippocampal and frontal regions which evolved to hyposynchronous FC at later stages in two different transgenic mouse models. Hypersynchronous FC was concomitant with excitatory/inhibitory misbalances of synapses and neurotransmitters, all of which were recovered by an anti-amyloid-beta immunotherapy treatment. To ensure a lack of interference of artefacts caused by genetic overexpression in transgenic models, we additionally assessed an amyloidosis knock-in model. Similar patterns of early hippocampal hypersynchrony and late-stage hyposynchrony were observed in this model. These studies established the usefulness of rsfMRI to detect and follow up early functional changes and treatment effects in AD pathology.



Url: https://www.uantwerpen.be/en/faculties/fbd/research/public-defence-of-a-phd/