Investigating the role of TREM2 in a mouse model of human dementia

Dementias constitute the group of neurodegenerative diseases that occur most frequently. Memory loss is a pronounced feature of most forms of dementia, but symptoms, onset, progression and pathology may vary largely between individuals. In Alzheimer’s disease (AD), the most common dementia, amyloid-β (Aβ) plaques and neurofibrillary tangles comprised of aberrantly phosphorylated microtube associated protein tau constitute the histopathological hallmark lesions. However, in other forms of dementia, tau pathology is present without overt amyloid pathology, amongst which, frontotemporal dementia (FTD) is the most prevalent form. As these diseases progress, tau pathology propagates in very distinct patterns along connected brain areas. The molecular mechanisms underlying this spread of tau pathology remain largely unknown. Neuroinflammation is observed in virtually all forms of dementia and several genetic risk factors with links to the brain immune system, have been identified in recent years. One such risk factor that has been linked to increased risk in developing AD and FTD is polymorphisms of the triggering receptor expressed on myeloid cells 2 (TREM2) gene. Interestingly, homozygous loss of function TREM2 mutations are causative for Nasu Hakola disease, an early onset form of dementia. Patients present with epileptic seizures, changes to neuronal network activity as measured by electroencephalography (EEG) and synaptic loss. All of these symptoms are commonly observed in AD and FTD patients. In this thesis I investigated the impact of TREM2 deficiency in a transgenic mouse model with tau pathology and studied the role of TREM2 in synapse function. TREM2 knock out (KO) mice were generated by CRISPR/cas9 mediated deletion of the start codon and then crossed with the tau transgenic model TAU58/2, expressing the P301S mutation on the 0N4R human tau isoform under the control of the murine Thy1.2 neuronal promotor. In tau transgenic mice, I found accelerated behavioural and cognitive deficits upon TREM2 loss, as well as enhanced levels of phosphorylated pathological tau and tangle like lesions. Interestingly, when investigating the stereotypical tau propagation in TREM2 KO mice, we found a significant higher amount of tau spreading. In addition, I have identified an increase in synaptic spine densities together with increased susceptibility to induced excitotoxic seizures in TREM2 KO animals. EEG recordings showed increased spontaneous epileptic discharges and aberrant neuronal network activity. Striatal cholinergic neurons were reduced, thus potentially creating an imbalance between excitatory and inhibitory signals. Taken together, this work highlights the importance of neuroinflammation in neurodegenerative disorders and provides evidence that TREM2 and microglia regulate important synaptic functions of the CNS.TREM2 has been shown to be a possible target for therapeutic intervention and multiple groups have started the development of TREM2 antibodies. This work provides important insights into which disease aspects might be regulated by TREM2 and could be modulated by therapeutic interventions in the future