Table 1.
A summary of a list of autophagy and mitophagy inducers and their biomedical activities.
| Mitophagy inducers | Chemical formula | Mechanism | Main effects on AD models | Reference |
|---|---|---|---|---|
| 5-aminoimidazole-4-carboxamide riboside (AICAR) | CH14N4O5 | AMPK activator. | Increases spatial memory and improves motor function in young and old mice. | [1] |
| Berberine | C20H18NO4+ | Berberine induces autophagy through the class III PI3K/Beclin-1/Bcl-2 pathway. Additionally, berberine triggers the enhancement of lysosomal activity, which effectively degrades LC3-Ⅱ-positive autophagosomes. |
Promotes Aβ clearance and inhibits its production, improves learning capacity and memory retentions and attenuates the hyperphosphorylation of tau in 3 × Tg AD mice. | [2] |
| Carbamazepine | C15H12N2O | Carbamazepine stimulates autophagy by a mechanism dependent on the myo-inositol levels and AMPK activation. | Alleviates memory deficits and cerebral Aβ pathology in APP/PS1 mice | [3,4] |
| Cinnamic acid | C9H8O2 | Cinnamic acid activates the nuclear hormone receptor PPARα to transcriptionally upregulate TFEB and stimulates lysosomal biogenesis. | Stimulates lysosomal biogenesis, decreases Aβ plaque burden and improves memory and behavioral performance in 5XFAD mice. | [5] |
| Everolimus | C53H83NO14 | Allosteric mTORC1-specific inhibitor. | Reduces human APP/Aβ and human tau levels and improves cognitive function in 3 × Tg AD mice. | [6] |
| Gemfibrozil and Wy14643 | C15H22O3 and C14H14ClN3O2S | Both of them are PPARA activators and can activate autophagy through TFEB pathaway. | Reverse memory deficits and anxiety symptoms and reduce level of soluble and insoluble Aβ in APP-PSEN1ΔE9 mice. | [7] |
| Gypenoside XVII | C48H82O18 | Gypenoside XVII enhances lysosome biogenesis and autophagy flux through TFEB activation. | Restores the spatial learning and memory, decreases soluble and insoluble fraction of Aβ and prevents the formation of Aβ plaques in the hippocampus and cortex of APP/PS1 mice. | [7,8] |
| HEP14 | C25H34O5 | HEP14 induces PKC-dependent activation of TFEB. | Reduces Aβ plaque formation in APP/PS1 mice. | [9] |
| Latrepirdine | C21H25N3 | Latrepirdine enhances mTOR- and Atg5-dependent autophagy. | Improves memory, degrades p62 and reduces the accumulation of insoluble Aβ42 in TgCRND8 mice. | [10] |
| Lithium chloride | LiCl | Lithium chloride induces autophagy by inhibiting inositol monophosphatase. | Restores the long-term spatial memory deficit and reduce brain Aβ levels in APP/PS1 mice. | [11,12] |
| Melatonin | C13H16N2O2 | Melatonin exhibits a beneficial effect on mitochondria by reducing the oxygen consumption rate, oxygen flux and membrane potential and, therefore, suppressing ROS production. | Reduces Aβ generation and modulates and maintains tau phosphorylation | [13–15] |
| Metformin | C4H11N5 | Metformin triggers autophagy through AMPK activation and subsequent inhibition of mTOR. | Decreases tau phosphorylation in human tau transgenic mice. Decreases Aβ influx across the blood–brain barrier, improves memory impairment under diabetic context. Attenuates spatial memory deficit, hippocampal neuron loss, enhances neurogenesis, decreases Aβ plaque load and chronic inflammation in APP/PS1 mice. | [16,17,18] |
| Nicotinamide mononucleotide(NMN) | C11H15N2O8P | NMN is a NAD+ precursor and mitophagy activator. | Reduces Aβ load, decreases p-Tau levels, improves cognitive and memory functions, reduces neuroinflammation and promotes microglia phagocytic activity in APP/PS1, 3xTgAD, Aβ and Tau models of C.elegans. | [19] |
| Nicotinamide riboside (NR) | C11H15N2O5 | NR is a NAD+ precursor and mitophagy inducer. | Increases NAD+ levels, promotes neurogenesis, improves cognition and reduces p-Tau and Aβ load and aggregation in Aβ model of C. elegans, 3xTgAD and APP/PS1 mice, APP-SH-SY5Y cells. | [19,20] |
| Nicotinamide(NAM) | C6H6N2O | NAM could enhance acidification of intracellular acidic organelles. In NAM-treated 3xTgAD mice the LC3-II/LC3-I ratio is reduced. | Improves cognitive performance, reduces Aβ and p-Tau pathologies and improves mitochondrial dynamics in 3xTgAD mice. Increses SIRT1 expression, which mediates the stress resistance signaling in NAM-treated 3xTgAD mice. | [21,22] |
| Ouabain | C29H44O12 | Ouabain enhances activation of TFEB through inhibition of the mTOR pathway and induces downstream autophagy-lysosomal gene expression. | Reduces the accumulation of phosphorylated tau in tau transgenic flies as well as improves memory inTauP301L mice. | [23] |
| Rapamycin | C51H79NO13 | Inhibition of mTOR signaling. | Decreases intraneuronal accumulation of Aβ, decreases brain levels of pathogenic Aβ42 and attenuates age-dependent accumulation of phosphorylated and aggregated tau in 3 × Tg-AD and PDAPP mice. Prevents synaptic failure induced by Aβ oligomers. There are ongoing clinical trials in humans. | [24–26] |
| Resveratrol | C14H12O3 | Resveratrol activates autophagy through the mTOR-ULK1 pathway and SIRT1/AMPK signaling pathway. | Decreases brain Aβ levels.Modulates Aβ cleveage preventing its oligomerization. The effects of resveratrol in neurodegeneration are widely described in a review. | [27,28] |
| Simvastatin | C25H38O5 | Simvastatin can activates LBK1-AMPK-mTOR signalling pathway. | Efficiently reduces levels of Alzheimer’s Aβ in yeast and reduces cerebral Aβ42 and Aβ40 levels in the cerebrospinal fluid and brain homogenate. | [29,30] |
| Spermidine | C7H19N3 | Spermidine triggers autophagy mainly by promoting AMPK phosphorylation and mitophagy via PINK1/Parkin pathway. | Reduces neuroinflammation and soluble Aβ in APP/PS1 mice and prevents Tau fibrillization in rTg4510 mice. | [31,32] |
| Temsirolimus | C56H87NO16 | Allosteric mTORC1-specific inhibitor. | Induces autophagy, reduces both Aβ and p-Tau and improves motor functions in several AD mouse models, such as APP/PS1, P301S and Tg30. | [33–35] |
| Tomatidine | C27H45NO2 | Tomatidine maintains mitochondrial homeostasis by modulating mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. | Counteracts age-related deterioration of muscle function in C. elegans through the activation of cellular stress responses against metabolic and oxidative stress. | [36] |
| Trehalose | C12H22O11 | Trehalose regulates autophagy by inducing rapid and transient lysosomal enlargement and membrane permeabilization. | Inhibits Aβ generation in APP23 mice and in HAW and 20E2 cells. | [37,38] |
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3. Li, L. et al. Autophagy enhancer carbamazepine alleviates memory deficits and cerebral amyloid-β pathology in a mouse model of Alzheimer's disease. 10, 433–441 (2013).
4. Vasconcelos-Ferreira, A. et al. The autophagy-enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease. Neuropathology and Applied Neurobiology48, e12763 (2022).
5. Chandra, S., Roy, A., Jana, M. & Pahan, K.J.N.o.d. Cinnamic acid activates PPARα to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer's disease mouse model. 124, 379–395 (2019).
6. Cassano, T. et al. Early intrathecal infusion of everolimus restores cognitive function and mood in a murine model of Alzheimer's disease. Exp Neurol311, 88–105 (2019).
7. Luo, R. et al. Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model. 16, 52–69 (2020).
8. Meng, X. et al. Gypenoside XVII enhances lysosome biogenesis and autophagy flux and accelerates autophagic clearance of amyloid-β through TFEB activation. 52, 1135–1150 (2016).
9. Li, Y. et al. Protein kinase C controls lysosome biogenesis independently of mTORC1. 18, 1065–1077 (2016).
10. Steele, J.W. et al. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. 18, 889–897 (2013).
11. Pan, Y. et al. Cognitive benefits of lithium chloride in APP/PS1 mice are associated with enhanced brain clearance of β-amyloid. Brain, Behavior, and Immunity70, 36–47 (2018).
12. Sarkar, S. et al. Lithium induces autophagy by inhibiting inositol monophosphatase. The Journal of cell biology170, 1101–1111 (2005).
13. Li, X.-C., Wang, Z.-F., Zhang, J.-X., Wang, Q. & Wang, J.-Z.J.E.J.o.P. Effect of melatonin on calyculin A-induced tau hyperphosphorylation. 510, 25–30 (2005).
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16. Chen, F. et al. Antidiabetic drugs restore abnormal transport of amyloid-β across the blood–brain barrier and memory impairment in db/db mice. 101, 123–136 (2016).
17. Ou, Z. et al. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. 69, 351–363 (2018).
18. Kickstein, E. et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proceedings of the National Academy of Sciences of the United States of America107, 21830–21835 (2010).
19. Fang, E.F. et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci22, 401–412 (2019).
20. Sorrentino, V. et al. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature552, 187–193 (2017).
21. Liu, D. et al. Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession. 34, 1564–1580 (2013).
22. Lautrup, S., Sinclair, D.A., Mattson, M.P. & Fang, E.F.J.C.m. NAD + in brain aging and neurodegenerative disorders. 30, 630–655 (2019).
23. Song, H.-L. et al. Ouabain activates transcription factor EB and exerts neuroprotection in models of Alzheimer's disease. 95, 13–24 (2019).
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31. Freitag, K. et al. The autophagy activator Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer’s disease mouse model. bioRxiv, 2021.2010.2028.466219 (2021).
32. Sandusky-Beltran, L.A. et al. Spermidine/spermine-N(1)-acetyltransferase ablation impacts tauopathy-induced polyamine stress response. Alzheimer's research & therapy11, 58–58 (2019).
33. Jiang, T. et al. Temsirolimus promotes autophagic clearance of amyloid-β and provides protective effects in cellular and animal models of Alzheimer's disease. Pharmacol Res81, 54–63 (2014).
34. Jiang, T. et al. Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance. Neuropharmacology85, 121–130 (2014).
35. Frederick, C. et al. Rapamycin ester analog CCI-779/Temsirolimus alleviates tau pathology and improves motor deficit in mutant tau transgenic mice. J Alzheimers Dis44, 1145–1156 (2015).
36. Fang, E.F. et al. Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci Rep7, 46208 (2017).
37. Liu, Y., Wang, J., Hsiung, G.-Y.R. & Song, W.J.M.N. Trehalose inhibits Aβ generation and plaque formation in Alzheimer’s disease. 57, 3150–3157 (2020).
38. Rusmini, P. et al. Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy15, 631–651 (2019).