The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer’s Disease and Schizophrenia
Abstract
1. Introduction
2. Neuropathological Processes in AD and Schizophrenia
2.1. Molecular and Morphological Signatures
2.2. Neuroinflammation and the Blood–Brain Barrier
2.3. Autophagy, Senescence, and Neurodegeneration
Feature | Alzheimer Syndrome | Schizophrenia Syndrome |
---|---|---|
Main Pathology | Amyloid-β plaques, tau tangles [37,90] | E/I imbalance, PVI/PNN disruption [91,92] |
Key Brain Regions | Hippocampus, cortex [93,94] | Prefrontal cortex, hippocampus [91] |
Autophagy-Related Genes | ↓ BECN1, ↓ ULK2, ↓ ATG5 [85,95] | ↓ BECN1, ↓ ULK2, ↑ BCL2, ↑ ADNP [85] |
Protein Aggregates | Extracellular Aβ, intracellular tau [94,96] | Synaptic/scaffolding protein buildup [85] |
Neuroinflammation | Microglial activation, RAGE/NF-κB signaling [97] | MMP9/RAGE pathway, oxidative stress [63,92] |
Cognitive Symptoms | Memory loss, executive dysfunction [98] | Working memory deficits, disorganized thinking [99] |
2.4. Divergent Cell Death Pathways in Schizophrenia and AD: From Apoptosis to Necroptosis
3. Biomarkers and Diagnostic Tools
3.1. S100B in Neurodegeneration and RAGE Interaction
3.2. Cognitive Impairment in Alzheimer’s Disease and Schizophrenia
3.3. Psychiatric Manifestations as Early Indicators of Alzheimer’s Disease and Schizophrenia
3.4. Differential Cognitive Impairment in Schizophrenia and Alzheimer’s: Psychiatric and Psychological Perspectives
3.5. Diagnostic Challenges and the Need for Comprehensive Evaluation in Schizophrenia and AD
3.6. Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio
4. Therapeutic Strategies
4.1. Current Treatments: Antipsychotics, Metformin, and Cholinesterase Inhibitors
4.2. Beyond Genetics: The Role of Environment and Epigenetics
4.3. Emerging Targets: mTOR, SYK, and S100B-RAGE
4.4. The Roles of Psychiatry and Psychology in the Context of Schizophrenia and Alzheimer’s Management
4.5. Translational Outlook and Personalized Medicine
5. Conclusions, Research Gaps, and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
5-HT2A | 5-hydroxytryptamine receptor 2A |
5xFAD | 5-familial Alzheimer’s disease mutations |
ABCA7 | Adenosine tri-phosphate binding cassette subfamily A member 7 |
AD | Alzheimer’s disease |
ADAM17 | A disintegrin and metalloproteinase 17 |
ADNP | Activity-dependent neuroprotective protein |
AGEs | Advanced glycation end-products |
AIWG | Antipsychotic-induced weight gain |
ALS | Amyotrophic lateral sclerosis |
AMPK | AMP-activated protein kinase |
APOE | Apolipoprotein E |
APP | Amyloid precursor protein |
ATG5 | Autophagy protein 5 |
Aβ | Amyloid-beta |
Aβ1-42 | Amyloid beta protein fragment 1-42 |
BBB | Blood–brain barrier |
BCL2 | B-cell lymphoma 2 |
BECN1 | Beclin-1 |
BIN1 | Bridging integrator 1 |
CACNA1C | Calcium voltage-gated channel subunit Alpha1 C |
CCL2 | C-C motif chemokine ligand 2 |
CD2AP | Cluster of differentiation 2-associated protein |
CLU | Clusterin |
CNS | Central nervous system |
CR1 | Complement receptor 1 |
CRP | C-reactive protein |
CSF | Cerebrospinal fluid |
CXCL10 | C-X-C motif chemokine ligand 10 |
DAMPs | Damage-associated molecular patterns |
DISC1 | Disrupted in schizophrenia 1 |
EEG | Electroencephalogram |
EPHA1 | Ephrin type-A receptor 1 |
FDA | Food and Drug Administration |
FPS-ZM1 | 4-Chloro-N-cyclohexyl-N-(phenylmethyl)-benzamide |
GABA | Gamma-aminobutyric acid |
GLP-1 | Glucagon-like peptide-1 |
GRIN2A | Glutamate ionotropic receptor NMDA type subunit 2A |
GWAS | Genome-wide association studies |
HMGB1 | High-mobility group box 1 |
ICAM-1 | Intercellular Adhesion Molecule-1 |
IL-1β | Interleukin-1 beta |
IL-6 | Interleukin 6 |
ITAMs | Immunoreceptor tyrosine-based activation motifs |
JAK/STAT | Janus kinase/signal transducers and activators of transcription |
LANDO | LC3-associated endocytosis |
LRP1 | Lipoprotein receptor-related protein 1 |
LRRK2 | Leucine-rich repeat kinase 2 |
MAPK | Mitogen-activated protein kinase |
MATRICS | Measurement and Treatment Research to Improve Cognition in Schizophrenia |
MCP-1 | Monocyte chemoattractant protein-1 |
mCRP | Monomeric C-reactive protein |
MLKL | Mixed lineage kinase domain-like |
MMP9 | Matrix metalloproteinase 9 |
MS | Multiple sclerosis |
MS4A | Membrane spanning 4-domains A |
mTOR | Mechanistic target of rapamycin |
mTORC1 | Mammalian target of rapamycin complex 1 |
mTORC2 | Mammalian target of rapamycin complex 2 |
NDDs | Neurodegenerative disorders |
NF-κB | Nuclear factor kappa B |
NMDA | N-methyl-D-aspartate |
NMDARs | N-methyl-D-aspartate receptors |
NRXN1 | Neurexin 1 |
PAMPs | Pathogen-associated molecular patterns |
PD | Parkinson’s disease |
PDAPP | Platelet-derived growth factor promoter driving expression of human amyloid precursor protein |
PET | Positron emission tomography |
PICALM | Phosphatidylnositol binding clathrin assembly protein |
PNN | Perineuronal nets |
PSEN-1 | Presenilin-1 |
PSEN-2 | Presenilin-2 |
pTau217 | Phosphorylated tau protein at amino acid position 217 |
PVI | Parvalbumin-positive interneuron |
RAGE | Receptor for advanced glycation end-products |
RIPK1 | Receptor-interacting protein kinase 1 |
RIPK3 | Receptor-interacting protein kinase 3 |
ROS | Reactive oxygen species |
S100B | S100 calcium-binding protein B |
SNCA | Synuclein alpha |
SYK | Spleen tyrosine kinase |
TNF-α | Tumor necrosis factor-alpha |
ULK2 | Unc-51-like kinase 2 |
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Russo, A.P.; Pastorello, Y.; Dénes, L.; Brînzaniuc, K.; Krupinski, J.; Slevin, M. The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer’s Disease and Schizophrenia. Int. J. Mol. Sci. 2025, 26, 6237. https://doi.org/10.3390/ijms26136237
Russo AP, Pastorello Y, Dénes L, Brînzaniuc K, Krupinski J, Slevin M. The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer’s Disease and Schizophrenia. International Journal of Molecular Sciences. 2025; 26(13):6237. https://doi.org/10.3390/ijms26136237
Chicago/Turabian StyleRusso, Aurelio Pio, Ylenia Pastorello, Lóránd Dénes, Klara Brînzaniuc, Jerzy Krupinski, and Mark Slevin. 2025. "The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer’s Disease and Schizophrenia" International Journal of Molecular Sciences 26, no. 13: 6237. https://doi.org/10.3390/ijms26136237
APA StyleRusso, A. P., Pastorello, Y., Dénes, L., Brînzaniuc, K., Krupinski, J., & Slevin, M. (2025). The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer’s Disease and Schizophrenia. International Journal of Molecular Sciences, 26(13), 6237. https://doi.org/10.3390/ijms26136237