Project Title : Targeting the MAPK-activated protein kinase 2 to reduce Aβ-induced neuroinflammation and cognitive impairment in the APP/PS1 mouse model

Project Registration Code : PN-III-P2-2.1-PED-2021-2241

Project Acronym: NeuroMAP Aβ

Project Scope and Objectives:

Targeting the MAPK-activated protein kinase 2 to reduce Aβ-induced neuroinflammation and cognitive impairment in the APP/PS1 mouse model Alzheimer’s disease (AD) is an irreversible, progressive brain disorder, which destroys the neuronal circuits underlying spatial and working memory, leading to cognitive decline. With up to a third of people born today set to develop the disease over their lifetime, it is one of the greatest challenges facing society.

A major goal in AD research is delivering early diagnosis and effective treatment before changes become irreversible. Early functional changes, such as dysregulation of excitatory glutamatergic signaling may offer targets for pharmacological intervention. There is, therefore, an urgent need to better understand the molecular mechanisms and signaling pathways underlying glutamatergic synaptic dysfunction associated with AD and how these changes manifest in cognitive deficits.

In recent years, mitogen activated protein kinase (MAPK)-signalling cascades have emerged as important mediators in AD pathology, with particular interest in the p38 MAPK pathway as a potential target for intervention. With p38 MAPK inhibitors showing a high burden of adverse effects, targeting downstream effectors may offer a more specific intervention. The MAP kinase-activated protein kinase, MAPKAPK2 (MK2) is activated by p38 MAPK and its canonical role mediating biosynthesis and production of pro-inflammatory cytokines, in particular tumour-necrosis factor alpha (TNFα) and interleukin 1-beta (IL-1β), in response to inflammatory signals is well-described. MK2 also mediates synaptic plasticity in the hippocampus, the functioning of which is necessary for spatial and working memory.

Here we will combine the generation of a novel mouse with the use of a specific inhibitor for MK2 to investigate the potential of targeting the MK2 cascade to ameliorate cognitive impairments associated with AD. To deliver this, we will: 1) generate a novel genetically modified mouse where MK2 will be knockout in the APPswe/PS1dE9 (APP/PS1) mouse model of AD and 2) perform intracerebroventricular (ICV) injection to deliver agents to inhibit MK2 activity in the APP/PS1 mouse. Control and treated wild-type (WT) and APP/PS1 animals will used to perform behavioural tests at 7 months of age (see preliminary data below showing that genetic deletion of MK2 in APP/PS1 mice prevented the over-activation of glutamatergic synaptic plasticity in the hippocampus of APP/PS1 when compared to WT littermate at 7 months).

After completion of behavioural tests, blood samples and brain tissue from all animals will be collected and used for biochemical and histological analyses. We expect that decreasing activity of the MK2 cascade will reduce the production levels of pro-inflammatory factors and ameliorate cognitive impairments that are observed in APP/PS1 mice at 7 months. Findings from this research has the potential to identify a novel mechanism through which neuroinflammation and synaptic plasticity are dysregulated 3 PN-III-CERC-CO-PED-3-2021 in the APP/PS1 mouse model of Alzheimer’s disease.

This novel mechanism may stimulate research on the bridge between neuroinflammatory and cognitive aspects of the disease. Further, the ability to target MK2 with inhibitors in vivo will indicate whether MK2 is an efficacious pharmacological target for ameliorating or delaying the onset of the cognitive symptoms