Second, the TFEB inducer 2-hydroxypropyl-β-cyclo- dextrin promoted the acidity of lysosomes in neurons 190 .
In regard to pharmacological manipulation, substances such as epigallocatechin and somatostatin promote the expression, secretion and (allosterically) catalytic activ- ity of IDE and neprilysin in parallel with an increase in the degradation of Aβ peptides 259,280 .
Indeed, clioquinol countered disruption of autophagy by chloroquine in retinal cells, reduced Aβ42 accumulation in CHO cells expressing APP and mutant presenilin 1 and diminished amyloid misfolding and aggregation in Tg2576 AD mice 196,197 .
The aminoimidazole derivative 5-aminoimidazole- 4-carboxamide ribonucleotide (AICAR) undergoes intra- cellular transformation to an AMP analogue that triggers AMPK-mediated autophagy 21,108 .
In addition, calcitriol (the active metabolite of vitamin D 3 ) elicited AMPK-dependent autophagy in a neurochemical lesion-induced model of PD 129.
Because the class III deacetylase NAD- dependent protein deacetylase sirtuin 1 (SIRT1) requires nicotinamide adenine dinucleotide (NAD) to sustain its activity, this positive regulator of autophagy may also be considered a sensor 24 .
SIRT1 is activated by AMPK- mediated increases in nicotinamide, and it drives the ALN by inhibiting mTORC1, inducing FOXO1 and FOXO3 and activating key regulatory proteins such as ATG5, ATG7 and LC3.
The di-glucose derivative trehalose inhibits the sol- ute carrier 2A (SLC2A) family of glucose transporters to promote AMPK-induced autophagy and reduce neurotoxic protein load, although it also exerts other actions downstream in the ALN 4,120 .
It also proved effective in cellu- lar models of PD, HD and AD 121,122 , as well as in mouse models of HD, AD and tauopathies, where it cleared aggregates, reduced neurodegeneration and ameliorated motor and cognitive performance 123–125 .
Sixth, Aβ42 compro- mises the function of AMPK to impede initiation of the ALN 67 .
Seventh, Aβ42 obstructs the UPS and CMA 47,68 .
The UPS and CMA are disrupted by neurotoxic proteins like Aβ42 and tau, hence, their early and preventive reinforcement prior to Aβ42 and tau accumulation may be critical.
The microtubule stabilizers paclitaxel and epothilone A countered Aβ42-induced cytoskeletal disruption — and moderated excessive UPR — in neurons 182 .
In a vicious circle, Aβ42 itself decreases IDE expression, although it may prompt its release from glia 254,259 .
Furthermore, epothilone D countered microtubule disruption and cognitive deficits in aged P301S/P19 AD mice 183 .
Lithium ions inhibit inositol monophosphatase to deplete inositol triphosphate.
This mechanism may be involved in its promotion of autophagy, reduction in cel- lular levels of α-synuclein, SOD1, Htt and tau 126 , ame- lioration of motor function in a P301L mouse model of tauopathy 127 and slowing of disease progression in SOD1 mice 128 .
For example, methylene blue coun- ters tau oligomerization and promotes autophagy 101,102 (Supplementary Table 4).
Other compounds that act through AMPK acti- vation include the antiaggregant methylene blue (Supplementary Box 1), which elevated levels of beclin 1, p62 and LC3, induced autophagy and suppressed tau in organotypic neuronal cultures and a mouse model of FTD 101,102 .
Third, acidic nanoparticles such as polylactic acid and poly(lactide- co-glycolide) increase acidification (BOX 3) .
Selenium deficits have been linked to AD, and thus it is interesting that seleno- methionine boosted ALN flux, from AMPK recruit- ment through autophagosome formation to lysosomal degradation, in the 3×Tg AD mouse model 112 .
Calpeptin, a cell-permeable calpain inhibitor, can also reduce Htt proteinopathy via induction of autophagy 103,105 .
In addition, the plant-derived alkaloid isorhynchophylline upregulated beclin 1 independently of mTORC1 and promoted autophagic clearance of α-synuclein, although its precise mechanism of action remains to be clarified 175 .
Indeed, clonidine and rilmenidine, two G i /G o -coupled α 2 -adrenergic receptor and imidazoline 1 receptor agonists, stimulate autophagy and cleared Htt in cellular 103 and animal models of HD 104 .
Likewise, temsirolimus reduced the accumulation of phosphorylated tau in SH-SY5Y cells and P301S tauopathy mice 137 .
It also removed cellular aggregates of mutant Htt and improved motor performance in a mouse model of HD, reduced α-synuclein aggregation and afforded neuroprotection in a lesion-based model of PD and depleted mutant ataxin 3 in a mouse model of supraspinal cerebellar ataxia type 3 (REFS133,138,139) .
It increased expression of βGCase, normalized autophagy and accelerated degradation of α-synuclein in a stem cell model of dopaminergic neurons derived from patients with PD bearing mutations in βGCase 200 .
Ambroxol, which also decreased ER stress in D. mela- nogaster 201 , reduced α-synuclein levels in overexpress- ing, transgenic mice 202 .
Cilostazol (a phosphodiesterase 3 inhibitor) clears Aβ42 from neuronal cell lines by promoting autophagy, upregulating beclin 1, ATG5 and LC3, downregulating mTORC1 and inducing lysosomal cathepsin B; these actions of cilostazol involve activation of SIRT1 as well as upstream Tyr172 phosphorylation of AMPK 108,162,163 .
Cilostazol improved cognition and reduced levels of Aβ42 and hyperphosphorylated tau following intra- cerebroventricular injection of Aβ25–35 into mice 162,163 .
The natural product curcumin induced macro- autophagy and protected rotenone-treated dopaminer- gic neurons 141 in addition to accelerating the elimination of mutant α-synuclein-A53T by repressing mTORC1 in a cellular model of early-onset PD, although it also exerts other actions such as inhibition of p300-mediated pro- tein acetylation and of aggregation 142,143 .
Pro-autophagic effects of curcumin are reflected in improved function in cellular and animal models of PD and AD, as well as reduced levels of α-synuclein aggregates 144 or Aβ and tau oligomers 145,146 .
Moreover, the flavonol fisetin stimulated auto- phagic degradation of phosphorylated tau in cortical neu- rons via mTORC1-dependent activation of TFEB and the cytoprotective transcription factor nuclear factor eryth- roid 2-related factor 2 (NFE2L2) 149 . Fisetin also reduced Aβ accumulation in an APP/PS1 mouse model of AD 150 .
Among compounds that inhibit HSP90, geldanamycin promoted elimination of both hyper- phosphorylated tau and oligomeric α-synuclein in cell lines 219,220 .
The antidiabetic drug metformin, a prototypical activator of AMPK, induced autophagy and increased longevity in mice 116 .
Moreover, reductions in levels of hyper phosphorylated tau and Aβ were seen in metformin- treated neurons 117,118 , while it blunted neuronal loss in a neurochemical lesion model of PD in mice 119 .
Inactivation of ABL1 with brain-penetrant nilotinib conferred neuroprotective autophagy in mouse models of PD 153 .
The ‘anti-ageing’ agent resveratrol is thought to indi- rectly recruit AMPK via activation of calcium/calmodulin- dependent protein kinase kinase 2 (CAMKK2), which, acting in synergy with Ca 2+ , exerts its effects via Thr172 phosphorylation 113 . This action, among others (below), is involved in its reduction of Aβ levels in N2a cells and neurons 114 and the elimination of Aβ and Htt in animal models of AD and HD 114,115 .
Resveratrol can stimulate SIRT1 via AMPK (see above), and it also possesses an AMPK-independent mode of SIRT1 recruitment that participates in blunting the neurotoxicity of Aβ25–35 fragments in PC12 cells 160 .
The multi-modal agent resveratrol induced the expression of ATG4 and promoted autophagosome formation.
Interestingly, resver- atrol downregulated RAGE as well as MMP9 — an effect that is related to decreased hippocampal load of Aβ42 (REF.297) .
The antibiotic rifampicin likewise promoted Aβ42 clearance by induc- ing BBB-localized LRP1 and P glycoprotein 1 (REFS273,292) .
Enhancing auto- phagy with rapamycin reduced levels of α-synuclein, FUS and Htt 130–132 .
Spermidine inhibits the acetylation of ATG7 and histone H3, while induc- ing beclin 1 via blockade of its cleavage by caspase 3 (REF.168) .
The less cytotoxic analogue of geldanamycin, 17-AAG, has improved brain penetrance. It decreased Aβ levels 223 , improved memory 224 and lowered tau in transgenic AD mice 224 . 17-AAG also reduced α-synuclein oligomers in H4 cells 220 .
Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 .
Finally, while physiological tau possesses KFERQ motifs and is degraded by CMA, aggregates, mutant forms and frag- ments interfere with CMA 45,47 .
Sixth, aggregates and mutant forms of α-synuclein disrupt the proteasome in dopaminergic neurons.
Third, apolipoprotein E allele 4 (APOE4), a major risk allele for sporadic AD, is associated with increased generation and accumula- tion of Aβ42 (REFS59,60) .
In addition to decreased degradation, one consequence is leakage of asparaginyl endopeptidase into the cytosol, where it generates toxic fragments of tau 61 .
Harnessing TFEB by 2-hydroxypropyl-β-cyclodextrin promoted clearance of proteolipid aggregates and α-syn- uclein in a cellular model of PD 195,204 .It also augmented the elimination of Aβ in a Tg19959/CRND8 mouse model of AD 173 .
An unusual approach to augmenting autophagosome formation is represented by the brain- penetrant autophagy enhancer 99 (AUTEN-99), which blocks myotubularin-related protein 14 (MTMR14, also known as Jumpy), a phosphatase that inhibits the phos- phoinositide 3-kinase (PI3K)-mediated generation of the autophagosome membrane (FIG. 3) . AUTEN-99 aug- mented autophagic flux in isolated neurons, increased markers of autophagy in mouse brain and slowed neuro- degeneration in D. melanogaster models of PD and HD 181 .
Fourth, activation of the lysosomal Ca 2+ channel mucol- ipin transient receptor potential channel 1 (TRPML1) with a synthetic agonist (ML-SA1) increased lysoso- mal Ca 2+ release, lowered pH and promoted Aβ clear- ance 191,192 .
Chronic administration of CGS-21680, a selective agonist of the AC-coupled adenosine A 2A receptor, restored proteasomal activity in cellular and murine models for HD via PKA-mediated Ser120 phosphorylation of the RPT6 component of the 19S subunit 231 .
Another HSP90 inhibitor, HSP990, has shown promise in lowering Htt aggregates and improving motor performance in two mouse models of HD 225 .
Another direct facilitator of AMPK, A769662, elicited autophagy and reduced the burden of Htt in a striatal cell line derived from knock-in mice expressing a humanized form of mutant Htt (exon 1 containing seven polyglutamine repeats) 111 .
One promising agent is the hydroxylamine deriva- tive arimoclomol, which increases the activity of HSP70 by augmenting transcriptional activity of HSF1 (REF.210) .
Tau, α-synuclein and TDP43 are substrates for CMA degradation, as are amyloid precursor protein (APP) but not amyloid-β fragment 42 (Aβ42) itself 3,45–47,48 .
CMA dysfunction in PD favours the accumulation of α- synuclein and leads to inactivation of the dopaminergic neuron survival factor, myocyte-specific enhancer factor 2D (MEF2D) 2,45,47,55 .
Htt is not efficiently cleared by CMA, and the same appears to hold for its fragments and mutant and post- translationally modified forms, although the precise role of CMA in Htt elimination remains to be more fully defined 2,45–47 .
Interestingly, the UPS is important for elimination of tau and other neurotoxic proteins in post synaptic dendritic compartments (a key site of spreading), where it plays a more general role favouring synaptic plasticity, den- dritogenesis and memory formation 49,52 .
Activity of the deacetylase SIRT1 declines with age, partially owing to limited availability of its co fac- tor, nicotinamide 24,56,156 .
Fourth, genetic mutations and anomalies of presenilin 1, a dominant negative gene linked to AD, are associated with reduced lysosomal v-ATPase-mediated acidifica- tion 40,63 , a compromised ALN and deficient mitophagy 64 .
Mutant Htt is cleared by autophagy, but it compromises the ALN because of decreased cargo load- ing and impaired autophagosome formation and trans- port 55,56,68,92 .
Some of these lead to an impairment of the ALN owing to reduced activation of beclin 1; another repercussion may be altered process- ing of APP, providing an unexpected link to AD 69,71–73 .
This kinase is classically inactivated by rapamycin, which binds to the modulatory protein 12 kDa FK506-binding protein (FKBP12; also known as FKBP1A).
Disruption of this Bcl-2–beclin 1 complex is an alternative approach for promoting autophagy, as achieved in mouse fibroblasts by the BH3 mimetic ABT-737 (REF.177) .
Activation of ULK1 triggers autophagosome nucleation through activating phospho- rylation of AMBRA and beclin 1 within the autophagy- specific PIK3C3 complex 10 (FIG. 3) .
Third, cellular inhibitor of apoptosis 1 (CIAP1; also known as BIRC2) specifically binds mutant SOD1 and drives it to proteasomal degradation.
Another kinase that activates the proteasome (RPT6 subunit) — and directs it to dendritic spines — is CAMKK2 (REF.227) .
Fifth, mutations in APP similarly disrupt endosomal and lysosomal func- tion, in part owing to accumulation of the β-secretase- generated, carboxy-terminal and Aβ42-containing fragment of APP called C99 (REF.66) .
The heterotrimeric serine/threonine kinase 5ʹ‑AMP‑ activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) trigger autophagy and repress mitophagy 3,10,20–23 (BOX 2; FIG. 3) .
AMPK is central to several mechanisms that trigger autophagy — most importantly, activating phosphoryla- tion of ULK1 (Ser317 and Ser777) and inhibitory phos- phorylation of mTORC1 (REFS21,31) .
One major strategy for promoting autophagy is the relief of its repression by mTORC1.
Conversely, mTORC1 inhibits ULK1 by Ser757 phosphorylation 3,4,31 .
mTORC1 also restrains autophagy by preventing nuclear translo- cation of TFEB 20 .
Finally, mirroring its inhibitory influence on the ALN, mTORC1 suppresses the UPS by impeding the formation and assembly of proteasomal subunits.
Tyrosine-protein kinase ABL1 is a proto- oncogene that negatively regulates autophagy, partly acting upstream of the RAC serine/threonine-protein kinase (AKT)–mTORC1 axis.
Activation of aquaporin 4 channels on perivascular astrocytes to aid the glymphatic elimination of cerebral Aβ and other toxic proteins is a potential strategy for stimulating clearance.
However, in light of common risk genes such as SQSTM1 (which encodes p62) and chromosome 9 open reading frame 72 (C9ORF72), FTD is increasingly linked to ALS 82,83 .
Mutations in C9ORF72 (the most prevalent risk gene for familial ALS and FTD) are likewise linked to disruption of the ALN, including interference with dynactin–dynein coordinated transport of autophagosomes along axons of motor neurons to the perikarya 82,88 .
Genetic knockdown of calpain 1 or calpain 2 or overexpression of their endogenous inhibitor, calpastatin, increased autophagy and cleared aggregates in SK-N-SH cells overexpressing a mutant form of Htt 103 .
Calpain inhibition by cal- pastatin or pharmacological agents also confers neuropro- tective effects in other NDA models, including improved clearance of tau, α-synuclein and SOD1 (REFS54,106,107) .
ALS shares many causal genes with FTD, including SQSTM1, CHMP2B, TBK1 (which encodes tank-binding kinase 1), OPTN (which encodes optineurin) and other genes associated with deficits in ALN and mitophagy.
Other transcription factors that posi- tively regulate autophagy include forkhead box protein O1 (FOXO1) and FOXO3 (REF.22) .
Fourth, homozygous mutations of lyso- somal β-glucocerebrosidase (βGCase; also known as GBA) provoke the LSD Gaucher disease, which is linked to decreased ALN flux, α-synuclein accumulation and a fivefold increase in risk of PD 43 (Supplementary Box 1).
Furthermore, expression of progranulin in the hippocampus of AD mice reduces the density of amyloid plaques by enhanc- ing the activity of neprilysin 281 .
Aβ42 and amylin (a pancreas-derived, AD-associated protein found in brain) are substrates for degradation by IDE, which also irreversibly traps Aβ42 and α-synuclein, preventing their aggregation and promoting ALN and UPS elimination 259 .
IDE also degrades and prevents the forma- tion of α-synuclein fibrils 259 .
Finally, the extracellular and intracellular serine protease neurosin (also known as KLK6) cleaves α- synuclein.
Nonetheless, overexpression of LAMP2A accelerated CMA-related clearance of α-synuclein and afforded pro- tection of dopaminergic neurons 45 , and several routes to potential pharmacological exploitation exist.
Second, the GTPase leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) is the most commonly mutated protein in late-onset, familial PD.
In addition, CMA is disrupted by sev- eral genetic mutations occurring in PD, including muta- tions in LRRK2 (REFS2,3,45–47,55,69,80) .
Similar to IDE, neprilysin catabolizes Aβ42, and its loss in mouse models of AD and in patients with AD alike also contributes to Aβ42 accumulation 253,256,260 .
For example, mutations in OPTN and TBK1 interfere with cargo loading 82,84,87 .
First, autosomal recessive forms of early-onset PD are associated with mutations in PTEN-induced putative kinase protein 1 (PINK1) and the E3 ubiquitin-protein ligase parkin; these mutations lead to deficits in the mitophagic removal of damaged mitochondria 69,70 (BOX 2) .
Like IDE and neprilysin, plasmin degrades Aβ42 and blocks Aβ42-induced toxicity, suggesting that the decrease in its levels in AD is involved in the evolution of AD 254,256,261 .
Plasmin also degrades α-synuclein to retard intercellular spreading 262 .
Furthermore, mutations in the gene encoding parkin and several other genes are linked to reduced UPS activity 2,56,69,79,80 .
Interestingly, genetic or pharmacological activation of RAB5 countered neurodegeneration in mouse C9ORF72 models of ALS and FTD 187 .
Supporting the relevance of sestrin 2, it has been shown to protect dopaminergic neurons from the neurotoxin rotenone via AMPK-transduced autophagy 247 .
Sestrin 2 over expression also prompted mTORC1-dependent autophagy in cortical neurons in a presenilin-knockout model of AD.
Third, α-synuclein mutations, triplications or excesses amplify the ALN burden, interfere with auto phagosome formation and irreversibly disrupt the lysosomal mem- brane 1,3,44,56 .
Conversely, repression is effected by signal transducer and activator of transcrip- tion 3 (STAT3) and possibly zinc-finger protein with KRAB and SCAN domains 3 (ZKSCAN3), although its role has been disputed 22,32 .
Unc-51-like kinase 1 (ULK1) is primarily an autophagy-initiating protein 3,10,19 , as is the mTORC1- suppressed transcrip- tion factor EB (TFEB), which orchestrates the synthesis of lysosomal and other proteins critical for maintaining ALN flux 20–23 .
Indeed, TFEB over- expression reduced amyloid plaques in a APP/PS1 mouse model 148 .
Second, while decr1eases in beclin 1 levels in AD remain to be confirmed, SIRT1 expression is diminished 24 .
ABL1 is overactivated in AD and tauopathies such as FTD 152 .
Cerebral levels of IDE are reduced in early AD and in mouse models of AD, whereas, mirroring AD amyloidosis, Aβ42 accumulates in mice genetically depleted of IDE.
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