Table 1.
Summary of data using different compounds in AD models. The putative mechanism, connecting or not autophagy, and the therapeutic effects were indicated.
| AD Mouse Model | Treatment | Molecular Mechanism | Phenotypic Effect | Ref. |
|---|---|---|---|---|
| T41 mice (mThy-1-hAPP751; APP V171I,K670M/N671L) | Genetic deletion of Becn-1 | Reduced autophagy | Increased amyloid-β levels and deposits. Increased neurodegeneration. |
[74] |
| Lentivirus-mediated expression of Becn-1 | Reduced Aβ levels | |||
| hAPP-J20 mice | Genetic deletion of cystatin C | Increased lysosomal cysteine proteases activity Rescued autophagic-lysosomal pathology |
Reduced Aβ levels and Aβ-associated cognitive deficits and behavioural abnormalities |
[75] |
| TgCRND8 mice (APP K670M, M671L, V717F) | Genetic deletion of cystatin B | Increased lysosomal cysteine proteases activity Rescued autophagic-lysosomal pathology |
Reduced amyloid-β40 and -β42 levels and prevented the development of learning and memory deficits | [76] |
| hAPP-J20 mice | Lentivirus-mediated expression of Cathepsin B | C-terminal truncation of Aβ42 | Reduced pre-existing amyloid deposits | [77] |
| APP/PS1 (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J) | Genetic deletion of one allele of Cathepsin D | Non reduced APP processing or degradation | No changes in Aβ levels | [90] |
| 3× Tg-AD mice (APPSwe /tauP301L/ PS1 knock-in) | Rapamycin | mTORC1 inhibition autophagy induction |
Improved learning and memory deficits and reduced amyloid-β and tau pathology | [72] |
| PDAPP mice (hAPP(J20)) | Rapamycin | mTORC1 inhibition autophagy induction chaperone levels increase |
Improved cognitive deficits and decreased amyloid-β42 levels | [78,79] |
| Tg2576 mice | Rapamycin | mTORC1 inhibition inhibition of ADAM10 |
Increased amyloid-β levels | [80] |
| TgCRND8 mice (APP K670M, M671L, V717F) | Latrepirdine | mTORC1 inhibition autophagy induction |
Improved learning behaviour and reduced amyloid-β42 and a-synuclein levels | [81] |
| APP/PS1 (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J) | Resveratrol | AMPK activation Autophagy induction |
Reduced amyloid-β40 and -β42 levels | [82] |
| APPswe/PS1dE9 | Tubastatin A and ACY-1215 | HDAC6 inhibition facilitated autophagic clearance of Aβ and hyperphosphorylated tau | alleviated behavioural deficits, altered Aβ load, and reduced tau hyperphosphorylation | [83] |
| APP/PS1 (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J) APPSwInd |
Z-Phe-Ala-diazomethylketone (PADK) | Increased Cathepsin B protein levels and activity Truncation of Aβ42 |
Reduced Aβ levels and Aβ-associated behavioural and synaptic deficits | [87] |
| APP/PS1 mice (APP K670M and M671L; PS1 M146L) | BDA-410 | Calpain inhibition * Restoration of normal phosphorylation levels of CREB |
Improved spatial-working and associative fear memories | [84] |
| Tg6799 (APP K670N/M671L, I716V, V717I; PS1 M146L/L286V) | L803-mts | GSK3 a/b inhibition Restoration of lysosomal acidification |
Reduced Aβ burdens | [88] |
| AβPPSwe/PS1A246E | Lithium | GSK3β inhibition Attenuated the autophagy activation, reducing APP processing |
Reduced Aβ total levels and deposits. Improved spatial learning and memory abilities. |
[91] |
| APP/PS1 mice | Trehalose | Altered the conformation Aβ to prevent its interaction with membranes Autophagy induction |
Reduced Aβ deposits, and total Aβ40 levels. Improved spatial memory and learning ability. | [92] |
| P301S tau mice | Trehalose | Autophagy induction | Reduced tau levels and deposits. | [93] |
| Tg2576 mice (APP Swe, K670N, M671L) | Trehalose | Autophagy induction | Reduced Aβ and tau deposits. | [94] |
| Tg6799 mice (APP K670N/M671L, I716V, V717I; PS1 M146L/L286V) | Metformin | AMPK activation and mTORC1 inhibition induces an abnormal accumulation of autophagosomes, promoting APP processing | Increased generation of Aβ | [84] |
| Tg-APP mice (APP 770 isoform K670N/M671L, E693Q, D694N) | Tyrosine kinase inhibitors (TKIs) (nilotinib, bosutinib) |
Increased parkin-Beclin1 interaction Autophagy induction |
Reduced Aβ levels. Cognitive improvement. |
[85,86] |
| 3 × Tg-AD mice (APPSwe/tau P301L/PS1 M146V) | Nicotinamide | Increased NAD+ biosynthesis, promoting autophagy and lysosomal acidification | Reduced Aβ and hyperphospholylated tau levels. Cognitive improvement. |
[95] |
| APP/PS1 mice (APP K594N/M595L; PS1-dE9) | 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran- 2(3 H)-one (3BDO) | Increased levels of insulin degrading enzyme and neprilysin. Suppressed autophagy via mTOR pathway |
Reduced Aβ levels. Prevented AD-like cognitive deficits. |
[96] |
| APP/PS1 mice (APP Swe/PSEN1dE9) | Carbamazepine | Autophagy induction unlikely via mTOR inhibition | Reduced amyloid plaque burden and Aβ42 levels. Alleviated spatial learning and memory deficits. |
[97] |
| 3× Tg-AD mice (APPSwe/tau P301L/PS1 M146V) | GTM-1 | Autophagy induction | Reduced Aβ levels and deposition. Alleviated spatial learning and memory deficits. |
[98] |
| APP-OSK mice Tg2576 mice Tau609 mice |
Rifampicin | Inhibition of oligomer formation preventing protein accumulation and autophagy dysfunction. | Reduced Aβ oligomer accumulation and tau hyperphosphorylation. Improved spatial memory. |
[99] |
| APP/PS1 mice (APP Swe/PSEN1dE9) | LX2343 | Suppression of JNK-mediated phosphorylation of APP(Thr668), and thus APP processing. PI3K/AKT/mTOR inhibition and induction of autophagy. |
Reduced Aβ levels and deposits. Alleviated spatial learning and memory deficits. |
[100] |
| 3 × Tg-AD mice (APPSwe/tau P301L/PS1 M146V) | Berberine | Autophagy induction. | Reduced Aβ levels and deposits. Improved spatial learning capacity and memory retention. |
[101] |
| 3× Tg-AD mice (APPSwe/tau P301L/PS1 M146V) | Selenomethionine (Se-Met) | Akt activation and GSK3β inhibition. Autophagy induction (AMPK-mTORC1 dependent). |
Reduced total and hyper-phosphorylated tau. Improved spatial memory |
[102] |