The mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signal transduction pathways that relay extracellular signals from membrane receptors to intracellular effectors controlling cell proliferation, differentiation, survival, and inflammatory responses. In the central nervous system, three principal MAPK modules — the extracellular signal-regulated kinases (ERK1/2), the c-Jun N-terminal kinases (JNK1/2/3), and the p38 MAPKs (p38α/β/γ/δ) — play distinct but interconnected roles in neuronal physiology and pathology. Aberrant activation of these cascades, particularly p38α MAPK and JNK, is now established as a key driver of neuroinflammation, tau hyperphosphorylation, synaptic dysfunction, and neuronal apoptosis across multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. [1]
Each MAPK cascade follows a three-tiered kinase architecture: a MAP kinase kinase kinase (MAP3K) phosphorylates and activates a MAP kinase kinase (MAP2K), which in turn phosphorylates and activates the terminal MAPK on its TxY activation motif. This amplification architecture enables signal specificity, integration of diverse upstream inputs, and threshold-dependent responses that are critical for distinguishing physiological signaling from pathological overactivation. [2]
The ERK1/2 pathway is classically activated by growth factors, neurotrophins (BDNF, GDNF, NGF), and synaptic activity through Ras GTPase → Raf (MAP3K) → MEK1/2 (MAP2K) → ERK1/2 (MAPK). In neurons, ERK signaling is essential for:
In neurodegeneration, the role of ERK1/2 is paradoxical: while ERK activation is generally pro-survival, chronic or aberrant ERK activation has been detected in neurofibrillary tangle-bearing neurons in Alzheimer's disease and in dopaminergic neurons in Parkinson's disease, where it may contribute to tau phosphorylation and oxidative stress. [4]
The p38 MAPK family, particularly p38α (MAPK14) and p38β (MAPK11), is activated by cellular stress signals including oxidative stress, pro-inflammatory cytokines (TNF-α, IL-1β), and pathogen-associated molecular patterns through MAP3Ks (ASK1, TAK1, MEKK3) → MKK3/MKK6 (MAP2K) → p38 (MAPK). In the brain, p38 MAPK is the primary stress-activated kinase implicated in neurodegeneration:
Conversely, the neuronal isoform p38γ has been shown to be neuroprotective in Parkinson's disease models, and its loss correlates with disease progression. Inhibition of p38α can restore p38γ function, representing a key therapeutic insight. [7]
The JNK pathway (JNK1/2/3) is activated by a broad range of stress signals through MAP3Ks (ASK1, MLK3, DLK, MEKK1) → MKK4/MKK7 → JNK. JNK3 is predominantly expressed in the brain and has been strongly implicated in neurodegeneration:
MAPK dysregulation is a prominent feature of AD pathology at multiple levels:
p38 MAPK activation: Phosphorylated p38 is elevated in AD brain tissue, co-localizing with neurofibrillary tangles and activated microglia surrounding amyloid plaques. The p38 MAPK-MK2/3 axis drives neuroinflammatory cytokine production that creates a self-amplifying cycle: Aβ activates microglial p38 → cytokine release → neuronal p38 activation → tau hyperphosphorylation → further microglial activation. [9]
JNK activation: JNK3 knockout mice show reduced Aβ levels, tau phosphorylation, and neuronal loss in AD models. JNK activation in AD correlates with Braak staging, increasing from early entorhinal involvement (Braak I-II) through limbic (III-IV) to neocortical stages (V-VI). [8:1]
ERK paradox: While ERK signaling supports neuronal survival, early and sustained ERK activation is detected in vulnerable hippocampal neurons in AD, potentially driving pathological tau phosphorylation. Phosphorylated ERK1/2 co-localizes with early-stage tangles but not mature tangles, suggesting a role in disease initiation. [4:1]
In Parkinson's disease, MAPK cascades are dysregulated in both dopaminergic neurons and surrounding glia:
In ALS, MAPK pathways are activated by mutant SOD1, TDP-43 aggregates, and C9orf72 repeat expansions:
Mutant huntingtin activates both JNK and p38 in medium spiny neurons:
p38α MAPK has emerged as one of the most promising kinase targets in neurodegeneration. Multiple classes of inhibitors are in development:
| Compound | Target | Stage | Key Results |
|---|---|---|---|
| Neflamapimod (VX-745) | p38α | Phase 2 (AD/DLB) | Improved episodic memory in early AD; reduced CSF tau. [11] |
| MW150 | p38α | Preclinical | Brain-penetrant; reduces neuroinflammation in AD/PD models |
| PRZ-18002 | p38 (PROTAC degrader) | Preclinical | Intranasal delivery; reduces pTau, Aβ, and microglial activation in 5xFAD mice. [12] |
| Skepinone-L | p38α | Preclinical | Selective; restores p38γ neuroprotection in PD models |
Rather than direct ERK inhibition, therapeutic strategies focus on restoring appropriate ERK signaling:
MAPK pathways do not function in isolation but interact extensively with other signaling cascades relevant to neurodegeneration:
🟡 Moderate Confidence
| Dimension | Score |
|---|---|
| Supporting Studies | 14 references |
| Replication | Multiple studies |
| Effect Sizes | Context-dependent |
| Contradicting Evidence | Some |
| Mechanistic Completeness | 60% |
Overall Confidence: 50%
Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010. ↩︎
Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011. ↩︎
MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci. 2004. ↩︎
Phosphorylated Map Kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells. Acta Neuropathol. 2001. ↩︎ ↩︎
Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer's Disease. Molecules. 2017. ↩︎
Phosphorylation sites on tau identified by mass spectrometry: differences in vitro between ERK2, JNK and p38, and GSK-3beta. J Neurochem. 2000. ↩︎
Inhibition of p38a MAPK restores neuronal p38g MAPK and ameliorates synaptic degeneration in a mouse model of DLB/PD. Sci Transl Med. 2023. ↩︎ ↩︎
JNK3 and neurodegeneration: roles in Alzheimer's Disease and beyond. J Mol Neurosci. 2019. ↩︎ ↩︎
p38-MAPK and CDK5 signaling pathways in neuroinflammation: potential therapeutic intervention in Alzheimer's Disease. Neural Regen Res. 2024. ↩︎
Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1-induced motor neuron death. Neurobiol Dis. 2007. ↩︎
Neflamapimod: clinical pharmacology and suitability to treat neurodegenerative diseases. Expert Opin Drug Metab Toxicol. 2023. ↩︎
Chemical knockdown of phosphorylated p38 MAPK as a novel approach for the treatment of Alzheimer's Disease. ACS Cent Sci. 2023. ↩︎
Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery. Signal Transduct Target Ther. 2025. ↩︎
Role of MAPK inhibitors in Alzheimer's Disease: role of brain kinases. Eur J Pharmacol. 2025. ↩︎