Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies
Abstract
:1. Introduction
2. Mismatch Between Senescence and Autophagy, a Critical Switch Initiating and Propagating Neurovascular Dysfunction and Blood–Brain Barrier Integrity
3. Mechanisms of Impaired Autophagy, Associated Neurodegeneration, and Novel Therapeutic Strategies for Protection of the Neurovascular Unit (NVU) and BBB
3.1. Senolytic Mechanisms and Pharmacological Intervention for Neurovascular Protection
3.2. Re-Normalization of Autophagy to Balance Senolysis, and Restoration of the NVU/BBB Microenvironment
3.2.1. Rapamycin and mTOR Inhibition, a Cornerstone of Autophagic Modulation
3.2.2. Metformin (AMPK Activator) Could Be a Multifaceted Therapeutic Agent in Autophagy, AD, and Anti-Aging
3.2.3. PDE5 Inhibitors as Novel Therapeutics in AD; Mechanisms and Evidence
3.2.4. Benzimidazole Derivatives: Repurposed for Autophagy and Senescence Modulation in AD
3.2.5. Acetylsalicylic Acid (ASA) in Autophagy, Senescence, and Neurodegeneration: Mechanisms of Action and Therapeutic Potential
3.2.6. A Note About Statins
4. Synergistic and Overlapping Signaling Molecules in Autophagic Modulation: A Case for Therapeutic Combination
4.1. Key Pathways and Unique Synergies
4.2. Therapeutic–Protective Composite
4.3. Further Hypothesized Combinational Strategies That Could Support AD Protection
4.4. A Targeted and Personalized/Stratified Approach
4.5. Limitations and Considerations for This Approach
4.6. Alternative Autophagy-Modulating Compounds for AD
5. Conclusions
6. Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
8-OHdG | 8-hydroxy-2′-deoxyguanosine |
AChE | Acetylcholinesterase |
AD | Alzheimer’s disease |
Akt | Protein Kinase B |
ALS | Amyotrophic Lateral Sclerosis |
AMPK | AMP-activated protein kinase |
APOE4 | Apolipoprotein E4 |
APP | Amyloid Precursor Protein |
ASA | Acetylsalicylic Acid |
AT-RvD1 | Aspirin-Triggered Resolvin D1 |
Aβ | β-amyloid |
BBB | Blood–Brain Barrier |
BChE | Butyrylcholinesterase |
BDNF | Brain-Derived Neurotrophic Factor |
BPH | Benign Prostatic Hyperplasia |
cGMP | Cyclic Guanosine Monophosphate |
CMA | Chaperone-Mediated Autophagy |
COX | Cyclooxygenase |
CREB | cAMP Response Element-Binding Protein |
ED | Erectile Dysfunction |
FLBZ | Flubendazole |
GGPP | Geranylgeranyl Pyrophosphate |
GSK3β | Glycogen Synthase Kinase 3 Beta |
HMGB1 | High mobility group box 1 protein |
HOMA-IR | Homeostasis Model Assessment of Insulin Resistance |
IL-6 | Interleukin-6 |
LC3 | Microtubule-associated protein 1 light chain 3 |
LTP | Long-Term Potentiation |
MAPK | Mitogen-Activated Protein Kinase |
MMP | Matrix Metalloproteinase |
mTOR | Mammalian Target of Rapamycin |
mTORC1 | Mammalian Target of Rapamycin Complex 1 |
NF-κB | Nuclear factor kappa B |
NO | Nitric Oxide |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
OXPHOS | Oxidative Phosphorylation |
PAH | Pulmonary Arterial Hypertension |
PD | Parkinson’s disease |
PDE5 | Phosphodiesterase-5 |
PGC-1α | Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha |
PPAR-γ | Peroxisome proliferator-activated receptor gamma |
ROS | Reactive Oxygen Species |
RPE | Retinal Pigment Epithelial Cells |
SASP | Senescence-Associated Secretory Phenotype |
SIRT1 | Sirtuin 1 |
SPMs | Specialized Pro-resolving Mediators |
TNF-α | Tumor Necrosis Factor alpha |
ULK-1 | Unc-51-Like Autophagy Activating Kinase 1 |
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Compound | Pharmacological Class | Mechanisms of Action | Cellular Targets/Effects |
---|---|---|---|
Rapamycin | mTOR inhibitor (macrolide antibiotic) | Inhibits mTORC1 → activates ULK1/ATG13 → promotes autophagy; upregulates Beclin-1, reduces p62, and modulates MEK/ERK pathway | Enhances autophagy in neurons; reduces Aβ and tau; improves synaptic plasticity; modulates microglial polarization |
Metformin | AMPK activator (antidiabetic biguanide) | Activates AMPK → inhibits mTORC1; induces CMA via TAK1–IKK pathway; stimulates SIRT1 and Nrf2 for antioxidant effects | Enhances autophagy (neurons and microglia); improves mitochondrial function; effects are cell-type and age dependent |
Navitoclax | Senolytic (Bcl-2/Bcl-xL inhibitor) | Induces apoptosis in senescent cells by inhibiting anti-apoptotic Bcl-2 family proteins | Eliminates senescent astrocytes and endothelial cells; restores neurovascular function and cognitive performance |
Sildenafil | PDE5 inhibitor | ↑ NO/cGMP → activates AMPK and eNOS → inhibits mTOR; activates CREB/BDNF; modulates NF-κB; increases autophagy markers (LC3, Beclin-1, ATG5) | Promotes autophagy in neurons and glia; improves blood flow, synaptic plasticity, and cognitive performance |
Tadalafil | PDE5 inhibitor | ↑ NO → activates SIRT1–PGC-1α axis → improves mitochondrial function and reduces ROS | Improves mitochondrial biogenesis and function in diabetic models; potential neuroprotective effects |
Mirodenafil | BBB-penetrant PDE5 inhibitor | Activates AMPK and autophagy; modulates cGMP/PKG/CREB, Wnt/β-catenin, GSK-3β, and glucocorticoid signaling | Enhances autophagy; reduces Aβ and tau; improves cognitive function and synaptic signaling |
FLBZ/Albendazole | Benzimidazole derivatives | Promote lysosomal clustering, JIP4–TRPML1 activation, enhance autophagosome–lysosome fusion; modulate NF-κB and NLRP3 pathways | Induce autophagy without mTOR inhibition; reduce SASP and neuroinflammation; clear protein aggregates |
Acetylsalicylic acid (ASA) | NSAID/COX-1/2 inhibitor | Induces autophagy via COX-2 inhibition and AT-RvD1 generation; inhibits NF-κB and NLRP3; activates TFEB via PPARα | Promotes clearance of Aβ/tau; reduces senescence and inflammation; preserves synaptic function |
Biomarker | Pathway Dysfunction Indicated | Relevant Drug | Therapeutic Action |
---|---|---|---|
↓ LAMP1, ↓ Cathepsin D | Impaired autophagosome–lysosome fusion | Benzimidazole derivatives | Enhance autophagic degradation via JIP4–TRPML1 pathway |
↑ IL-6, ↑ TNF-α, ↑ MMPs | Chronic inflammation and SASP activation | ASA and benzimidazoles | Suppress NF-κB signaling and SASP factors |
↑ NF-κB activation (p65 subunit) | Inflammatory and senescence pathways | ASA and benzimidazoles | NF-κB inhibition and anti-inflammatory action |
↓ AMPK activation, ↑ mTORC1 activity | Impaired autophagy initiation and metabolic stress | Metformin | AMPK activation and mTORC1 inhibition to restore autophagy |
↑ 8-OHdG, mitochondrial DNA damage | Oxidative stress and mitochondrial dysfunction | Metformin | Nrf2-mediated antioxidant defense and mitochondrial support |
↑ HOMA-IR score, insulin resistance | Metabolic dysfunction | Metformin | Improvement of insulin sensitivity and energy homeostasis |
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Cordos, B.; Tero-Vescan, A.; Hampson, I.N.; Oliver, A.W.; Slevin, M. Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies. Pharmaceuticals 2025, 18, 829. https://doi.org/10.3390/ph18060829
Cordos B, Tero-Vescan A, Hampson IN, Oliver AW, Slevin M. Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies. Pharmaceuticals. 2025; 18(6):829. https://doi.org/10.3390/ph18060829
Chicago/Turabian StyleCordos, Bogdan, Amelia Tero-Vescan, Ian N. Hampson, Anthony W. Oliver, and Mark Slevin. 2025. "Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies" Pharmaceuticals 18, no. 6: 829. https://doi.org/10.3390/ph18060829
APA StyleCordos, B., Tero-Vescan, A., Hampson, I. N., Oliver, A. W., & Slevin, M. (2025). Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies. Pharmaceuticals, 18(6), 829. https://doi.org/10.3390/ph18060829