Identifying Targets for Alzheimer’s Disease: MAPK14

Alzheimer’s disease (AD) represents 60-70% of dementia cases worldwide.¹ By 2050, global AD cases are projected to exceed 150 million.² AD is characterized by protein aggregation, plaque deposition, and the presence of neurofibrillary tangles in the brain.³ Cognitive decline, a primary symptom of AD, manifests years or even decades prior to clinical diagnosis. The challenge lies in the early detection and effective treatment of AD, given its subtle onset and complex pathophysiology.

Currently, AD is managed through symptomatic treatments aimed at mitigating cognitive decline and related symptoms. In 2023, the FDA-approved antibody drug, Lequembi, emerged as a significant advancement, targeting amyloid-beta to reduce brain amyloid plaques and decelerate cognitive deterioration. ⁴

Despite progress, there is no cure for AD, necessitating on-going research to develop effective treatments. Central to this endeavor is the identification of molecular and biological targets that can pave the way for potential disease-modifying therapies. Here, we have used Causaly to explore potential targets for AD.

With over 200,000 articles published on AD, drug discovery researchers face challenges in identifying a starting point for their investigations. Causaly helps manage this data overload by machine-reading the literature and extracting target-disease relationships. This enables scientists to prioritize potential drug targets with greater efficacy.

MAPK14 is a protein kinase involved in the regulation of cellular stress responses, in addition to controlling cell proliferation and survival. Deletion of MAPK14 in an APP-PS1 transgenic AD mouse model was shown to increase autophagy and reduce amyloid plaque pathology.⁵ More recently, the deficiency of MAPK14 in all myeloid cells, not just microglia, triggers efficient Aβ clearance in the brain and improves cognitive function of APP‐transgenic mice.⁶ Therefore, MAPK14 could be a potential therapeutic strategy for AD.

Understanding the mechanism of action of MAPK14 is pivotal for evaluating the efficiency of a target’s inhibition from a treatment perspective. By utilizing Causaly, pathways affected by MAPK14 inhibition in AD can be identified.

Simvastatin was shown to regulate ERK/MAPK signaling in hippocampal cells, leading to increased expression levels of phospho-ERK/MAPK in a triple-transgenic AD mouse model.⁷ Another study showed that the inactivation of MAPK14 alleviated endophilin A1- and Aβ-induced synaptic loss and deficits in vesicle recycling and hippocampal LTP.⁸ In addition, the activation of MAPK14 via endophilin A1 was reportedly responsible for Aβ-induced aberrant mitochondrial function and oxidative stress.⁸

To understand similarities and differences in the mechanisms of action of different targets of interest, a comparative analysis can be performed in Causaly. Here we compared APP and MAPT (two of the most studied AD targets) and MAPK14 on a pathway level.

Shared pathways affecting all three targets include apoptosis and mitophagy. The overexpression of APP, MAPT and MAPK14 induce oxidative stress and apoptosis, leading to neurodegeneration. Interestingly, studies have shown that the p38 MAPK pathway is involved in the activation of melanogenesis through elevation of microphthalmia-associated transcription factor expression.⁹

Target identification remains pivotal in Alzheimer’s research. Pinpointing precise molecular and biological targets have the ability to revolutionize treatment approaches. By understanding and prioritizing these targets, we edge closer to more effective therapies, offering hope to millions affected by this debilitating neurodegenerative disorder.