Darius Miranda-Sohrabji

Background: Alzheimer’s Disease (AD) results in a profound loss of cognition and memory with increasing dependency upon caregivers to undertake activities of daily living. The hallmark pathological changes of AD are extracellular deposits of beta-amyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau.¹ Currently, pharmacotherapy for AD focuses primarily on management of symptoms. A potential therapeutic target that addresses chronic neuroinflammatory processes present in AD is p38 mitogen-activated protein Kinase (p38 MAPK).  P38 MAPK is a stress-associated kinase that is activated in response to oxidants, inflammatory cytokines, and A-beta.^1,2 P38 MAPK is localized and upregulated near lesion sites in the AD brain, distinguishing this pathway as a specific target for therapeutic intervention.^2,3

Objective: This narrative review investigates a potential mechanism for therapeutic effects of inhibiting the proinflammatory p38 MAPK pathway on the pathological protein accumulation and disrupted immune function of AD.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the following keywords: “Alzheimer’s Disease” “Inflammation” “p38 MAPK” “microglia” “tau protein” “beta amyloid”

Results: Studies reveal that inhibition of p38-MAPK alleviates overall cerebral beta-amyloid and tau burden in transgenic mice expressing these pathological proteins.¹ This is paired with an increase in mature-spine density in hippocampal neurons and a reduction of cognitive impairment.¹ Further investigation finds that the chemokine-like receptor 1 (CMKLR1) axis induces migration of microglia via the p38-MAPK pathway. Inhibition of p38 MAPK significantly reduces CMKLR1-induced microglial polarization and colocalization with A-beta deposits.⁴ Microglial activation of p38 MAPK occurs in response to extracellular tau and independently of microglial phagocytosis of tau.⁵ Importantly, inhibition of p38 MAPK reduces susceptibility of microglia to tau-mediated cytotoxicity.⁵ This occurs in spite of the simultaneous increase of microglial phagocytosis and lysosomal processing of tau protein when p38 MAPK is blocked.⁵

Conclusion: While p38 MAPK mobilizes microglia to lesion sites, it impedes their ability to clear protein aggregates effectively. Tau and A-beta activate genes in this pathway, sustaining microglial proinflammatory status and susceptibility to cytotoxic protein effects without resolution. Consequently, protein aggregates accumulate, causing neuronal death and compromising brain immune-mediated clearance mechanisms. In clinical trials, neflamapimod, a p38 MAPK inhibitor, showed promise in reducing amyloid and improving cognition in mild AD, but larger trials did not confirm significant effects compared to placebo.⁶ The crucial role of p38 MAPK in AD-related protein deposition necessitates further trials to understand the effects of inhibition across different AD stages and populations.

Works Cited:

1. Schnöder L, Gasparoni G, Nordström K, et al. Neuronal deficiency of p38α-MAPK ameliorates symptoms and pathology of APP or Tau-transgenic Alzheimer’s mouse models. FASEB J. 2020;34(7):9628-9649. doi:10.1096/fj.201902731RR
2. Hensley, K., Floyd, R.A., Zheng, N.-Y., Nael, R., Robinson, K.A., Nguyen, X., Pye, Q.N., Stewart, C.A., Geddes, J., Markesbery, W.R., Patel, E., Johnson, G.V.W. and Bing, G. (1999), p38 Kinase Is Activated in the Alzheimer’s Disease Brain. Journal of Neurochemistry, 72: 2053-2058. https://doi.org/10.1046/j.1471-4159.1999.0722053.x
3. Muraleva NA, Stefanova NA, Kolosova NG. SkQ1 Suppresses the p38 MAPK Signaling Pathway Involved in Alzheimer’s Disease-Like Pathology in OXYS Rats. Antioxidants (Basel). 2020;9(8):676. Published 2020 Jul 28. doi:10.3390/antiox9080676
4. Chen Y, Liu Z, Gong P, et al. The Chemerin/CMKLR1 Axis Is Involved in the Recruitment of Microglia to Aβ Deposition through p38 MAPK Pathway [published correction appears in Int J Mol Sci. 2022 Dec 28;24(1):]. Int J Mol Sci. 2022;23(16):9041. Published 2022 Aug 12. doi:10.3390/ijms23169041
5. Perea JR, Bolós M, Cuadros R, et al. p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function. Mol Neurobiol. 2022;59(3):1632-1648. doi:10.1007/s12035-021-02715-0
6. CLINICAL TRIAL: Prins ND, Harrison JE, Chu HM, et al. A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer’s disease. Alzheimers Res Ther. 2021;13(1):106. Published 2021 May 27. doi:10.1186/s13195-021-00843-2