PubMed: 29758300

Alzheimer's disease and the autophagic-lysosomal system.
Neuroscience letters
Sproul AA | Hernández N | Chung KM | Yu WH

Evidence 86f82e7c74

Under starvation or stress, TFEB translocates to the nucleus and binds the CRE element to promote expression of macroautophagy and lysosomal genes [88].

Evidence f68b9c42e8

Protein clearance in animal models has been successfully demonstrated using several small molecules and drugs that enhance induction of macroautophagy reduces AD-relevant pathology, including rapamycin in 3xTGAD mice [32] and temsirolimus in P301S transgenic mice [156] and trehalose in APP/PS1 and P301S MAPT transgenic mice [157,158].

Evidence 1d0e5284df

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32]

Evidence a836ae9b17

This inhibition of Aβ secretion during macroautophagy deficiency results in aberrant cytosolic accumulation of Aβ, which ultimately evokes neurodegeneration accompanied with memory loss.

Evidence a2b48f2557

Although exact relations remain unknown, it was reported that Aβ can induce a cascade that results in phosphorylation and subsequent deposition of TDP-43 in the cytosol [70]

Evidence 6f78378ea2

Overexpression of PICALM in APP/PS1 mice substantially elevates Aβ levels, whereas knockdown reduces the Aβ plaque load, respectively [98]

Evidence b235a5f4e0

Identified as a candidate susceptibility gene for AD by GWAS [116], reduced level of SORL1 has been consistently correlated with brain Aβ levels [118,119].

Evidence 710a37c2bc

Furthermore, presenilin-1, the most common mutation associated with early-onset familial AD (FAD), plays an essential role in calcium homeostasis and maintaining acidic lysosomal pH, with FAD-associated mutations disrupting calcium-dependent vATPase function in lysosomes [7,18–20]

Evidence 4ea7de51da

Methylene blue, a contrast agent that can reduce tau misfolding, has also been shown to induce macroautophagy, as indicated by elevated Beclin 1 and LC3-II levels and reduced tau and p62 levels in organotypic neuronal cultures and a mouse model of FTD [159]

Evidence 6b95a9cfd3

Sphingolipids are also strongly implicated in AD pathology, with upregulated levels of ceramide, a key component in sphingolipid metabolism, detected in the early phase of AD [80].

Evidence 50e657218e

Cellular cholesterol can directly impact the level of Aβ, as decreases in cholesterol levels inhibit the generation of Aβ peptides through direct modulation of γ-secretase activity [78,79].

Evidence 95d72e5a43

Paclitaxel reversed Aβ-induced microtubule disruption and restored autophagosomal transport in neurons [161], while a similar compound, epothilone D/BMS-241027, reduced tauopathy and improved cognition in P301S transgenic mice [162] although the compound did not progress beyond Phase I clinical testing

Evidence 099ad72efa

In addition to their structural role in membranes, lipids are essential in the maintenance of cellular energy homeostasis as well as regulation of intracellular signaling pathways

Evidence 3ccbf5cf3c

Decreased triglyceride breakdown upon macroautophagy inhibition and impairment in macroautophagy by lipid supplementation demonstrates reciprocally interrelated regulation of autophagy and lipids [72]

Evidence 4e0caebe0c

Lipid biology can also impact proteinopathy, with strong evidence that Aβ metabolism is modulated by lipids

Evidence 1dde898580

In addition to the direct modulation of protein generation, lipids can also influence the levels of proteins through autophagic clearance; for instance, increasing lipid contents has been shown to impair autophagy [72].

Evidence 000492d901

For instance, rapamycin, an inhibitor of the Ser/Thr protein kinase mammalian target of rapamycin (mTOR), improves cognitive function and reduces Aβ in AD mouse model by enhancing autophagic flux [23].

Evidence b23d047703

Modulation of mTOR can influence the levels of tau, with upregulation increasing tau phosphorylation and accumulation by reducing autophagic clearance [87], and conversely, pharmacological treatment with rapamycin reducing tau levels and rescuing motor deficits in the Tau P301S mice [53]

Evidence d639aea648

The finding of reduced Aβ generation when conversion of sphingomyelin to ceramide is blocked further substantiates the crucial involvement of sphingolipids in Aβ metabolism through modulation of γ-secretase [81,82]

Evidence 494d6a47a6

For example, levels of Beclin 1, a key component of the class III type phosphoinositide 3-kinase/VPS34 complex essential to the pre-autophagosomal structure (PAS), has been suggested to be reduced in AD brains [16,17], with Rohn et al. demonstrating the cleavage of Beclin 1 by caspase-3 in the AD brain and colocalization of the cleaved product with NFTs [16].

Evidence 5f989971aa

Other studies have also demonstrated the accumulation of autolysosomes in the AD brain and experimentally when lysosomal proteolysis is compromised via genetic knockdown of specific cathepsins or use of pharmacological inhibition of lysosomes [2,3,15]

Evidence 80260d6ddb

Mitochondria are instrumental in the regulation of energy metabolism, and impairment in mitochondrial function has been implicated in the pathogenesis of AD, leading to the mitochondrial cascade hypothesis of AD [121].

Evidence a7308cffd4

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy.

Evidence b3fbcdad3d

Furthermore, the membrane bilayer lipid can influence protein aggregation and subsequent tau pathology, with recent studies showing that tau binds to the membrane, which has subsequent effects on the formation of fibrillary tau aggregates [85,86].

Evidence 714e4c204a

While AD is generally considered a disorder with two proteinopathies, other protein aggregates are also seen in AD, like α-synuclein

Evidence 2096813afc

First identified as a nonamyloid component of Aβ plaques in the AD brain, α-synuclein aggregates are detected in the majority of the brains of patients with AD [56,57].

Evidence a44a679491

Misfolded α-synuclein proteins form insoluble oligomers, which in turn lead to the cascade of pathogenic neurotoxicity-induced responses such as neuroinflammation and cell death [55]

Evidence 610778d113

The presence of aberrant protein aggregates is common to neurodegenerative diseases

Evidence 59891841fa

Defective chaperone-mediated autophagy (CMA), a type of autophagy that targets proteins with a specific KFERQ-like motif recognizable to its chaperones, plays a significant role in aggregate formation of disease-related proteins [28].

Evidence c529275ef2

Evidence suggests that CMA can degrade tau via the chaperone heat shock cognate of 70 kDa (Hsc70), which recognizes KFERQ-like motifs and transfers its substrates via LAMP-2 into the lysosome [47]

Evidence 6aa056ffb8

Cuervo et al. have revealed a distinct interaction of wild-type and mutant α-synuclein proteins with CMA [64]

Evidence 90b1a9a843

While wild-type α-synuclein protein efficiently clears via CMA, the pathogenic A53T and A30P variants remain bound to LAMP-2, blocking lysosomal degradation by preventing binding of other substrate complexes to the receptor [64].

Evidence 2d6a7f1ba5

Such evidence of lysosomal proteolytic failure in AD brain further strengthens the concept that impaired macroautophagy in AD is a critical event

Evidence 9d401ad5c0

Even early autophagic activation may become impaired due to progressively diminishing lysosomal clearance of substrates.

Evidence cb687d8942

With neurons profoundly relying on macroautophagy for clearance of toxic protein aggregates, impairment in the proteolytic systems ultimately results in progressive neuronal death, a common feature in several neurodegenerative diseases [27].

Evidence 214ffcb092

Impairment in the UPS is cardinal to the development of neurodegeneration, in part because of its reciprocal interplay with protein aggregation

Evidence 08f6d176a4

For instance, phosphorylated insoluble tau proteins dampen 26S proteasome activity, while activation of the UPS attenuates tauopathy [27]

Evidence 86cc97c128

These experimental differences may be attributed to the intricate interplay between the UPS and autophagy, as α-synuclein is degraded by both proteolytic systems [62,63].

Evidence 59915fbc8d

Robust AV accumulation in dystrophic neurites from biopsy tissues from patients with AD implicate a compromised state of autophagic flux

Evidence 05bb0152e7

Although the UPS is accountable for the degradation of up to 80–90% of proteins, misfolded proteins and aggregates are too large to be processed through the proteasome barrel and can impede UPS function by physical occlusion, leaving autophagic-lysosomal breakdown as the only effective pathway to clear these proteins [25,26]

Evidence b8b6c00c34

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45].

Evidence eb16622129

TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89].

Evidence 9ad5382e61

Decreased autophagy in the diseased brain may contribute to aberrant lipid accumulation that occurs along with an increased incidence of the metabolic syndrome in aged humans [76]

Evidence 08cf149d03

While autophagic-lysosomal degradation is more commonly associated with protein degradation, it serves to degrade all cellular material including carbohydrates and lipids.

Evidence 44ff6147f7

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87]

Evidence 98e78f42db

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38]

Evidence b05a256a60

Since Nixon and colleagues first reported the pathological evidence of defective macroautophagy in EM images in the AD brain, similar observations have been made in cellular and animal models of AD [2,3,7,14]

Evidence 0489d0d41f

Defects in macroautophagy in AD are supported by additional lines of evidence

Evidence 8ad04ffac2

Maintenance of neuronal macroautophagy can counteract AD pathology [22,23].

Evidence 6ca753fe0c

Lastly, macroautophagy, but not UPS or CMA can clear protein aggregates.

Evidence b3520f2ea8

Increased Aβ generation and accumulation in lysosomes suggest that Aβ metabolism, at least partially, is regulated by macroautophagy [3,14,32–34].

Evidence 15c41453f9

In line with this, reduced Beclin 1 levels, as seen in AD models [16], increase the levels of intracellular and extracellular Aβ peptides, supporting the role of macroautophagy in the generation and degradation of Aβ [33,35].

Evidence 736677bedb

Compromised macroautophagy, via the genetic suppression of Atg7, leads to the blockade of Aβ secretion and contributes to the subsequent diminution in extracellular Aβ plaque load

Evidence 4bca3daff1

Wang et al., using an N2a neuroblastoma cell line that expresses the repeat domain of tau with an FTD-17 mutation (TauRDΔK280), has demonstrated that tau aggregates can be degraded by macroautophagy [48]

Evidence 81a480441c

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154]

Evidence 2220041162

However, recent work provides direct evidence that PICALM can also modulate macroautophagy, via its role in SNARE endocytosis to clear tau aggregates [102].

Evidence 56c7c180c6

Aβ peptides originate from the transmembrane protein amyloid precursor protein (APP) which undergoes sequential cleavage via two distinct pathways by the enzyme complexes β- and γ-secretase [31]

Evidence cb29ceb57e

Since the initial finding of proteasome-dependent degradation of α-synuclein [58], significant efforts have been made to clarify the modes of α-synuclein metabolism

Evidence 255a4a493a

Cytosolic tau is highest in density in membrane-rich axons and growth cones where lipid interaction with cytosolic tau may contribute to fibrillary tau aggregation [84].

Evidence 4fc1f2e66a

Tau serves an important function by enabling microtubules to connect with cytoskeletal components and facilitates anterograde and retrograde axonal transport of vesicles and organelles [39].

Evidence 246e16ad56

Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP).

Evidence 0e617103f4

NBR1 colocalizes with tau and has primary sequence domains for binding [52].

Evidence f3053f4c4f

In a more recent GWAS investigation, TREM2 (triggering receptor expressed on myeloid cells 2) was identified as one of the markers strongly associated with increased levels of tau and phosphorylated tau in cerebrospinal fluid from AD patients [91].

Evidence bc22979fae

While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29].

Evidence 43c2afe659

Recent clinical and immunohistochemistry studies demonstrate the contribution of α-synuclein in the development of AD pathology

Evidence bc4bdcf536

One intriguing molecule that interacts with VPS35 is SORL1, a VPS10P-domain receptor protein that has been linked to autosomal dominant early-onset AD [116,117].

Evidence 40fe7c5561

VPS35, one of the retromer-related genes identified from GWAS datasets on AD [110], regulates TREM2’s function in microglia [111].

Evidence 45b0dd1f13

Another modulator of A-LS implicated in AD pathology is transcription factor EB (TFEB), a master regulator of lysosome biogenesis

Evidence 608e6e9d1f

Activation of PTEN, another inducer of macroautophagy, by TFEB is indispensable for this TFEB-mediated increase in macroautophagy [89]

Evidence 2bdb8b5b16

However, in another study, iPSC-derived tau A152T and MAPT IVS 10+16 (a tau splice mutant) cortical neurons had increased cell death in response to rapamycin treatment, although basal cell death was ∼10 times higher in these tau mutants relative to controls, making interpretation of the work difficult [134].

Evidence 23b46da3f8

For example, in tau A152T iPSC-derived cortical neurons, total and phosphorylated Tau levels are elevated, particularly the insoluble forms [133], which is associated with decreases in UPS function as measured by total polyubiquitinated proteins and an upregulation of macroautophagy markers.

Evidence 698ea32fd7

For instance, adenosine monophosphate- activated protein kinase (AMPK) phosphorylates ULK1 and inactivates mTOR through the raptor and tuberous sclerosis complex (TSC2).

Evidence d906360270

For instance, ApoE4–an important determinant of cholesterol metabolism and the strongest genetic risk factor for sporadic AD – regulates Aβ degradation [77].

Evidence fde0704235

Tau phosphorylation, the major disease-related post-translational modification, is highly regulated by glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5), mitogen-activated protein kinase (MAPK) and other kinases.

Evidence 8c0b75a126

For example, Beclin 1 suppression results in impaired microglial phagocytosis of Aβ and reduced recycling of TREM2 [108].

Evidence 3c5067804b

BIN1 is involved in the endocytosis and the endosomal sorting of membrane proteins

Evidence c423a41bb8

Similar to PICALM, BIN1, due to its role in endocytosis and trafficking, is implicated in APP metabolism [103].

Evidence 6b0a46f7e5

Suppression of BIN1 disrupts cellular trafficking of BACE1 and reduces BACE1 lysosomal degradation, leading to increased Aβ production [103].

Evidence 8e43decf4b

Higher expression of BIN1 has been reported in AD brains, and suppression of BIN1 reduces tau toxicity, suggesting BIN1 involvement in tau pathology, as well [104].

Evidence d9d7a4e3b7

However, when tau becomes hyperphosphorylated, it detaches from microtubules and aggregates, resulting in depolymerization of microtubules and formation of insoluble tau deposits [40]

Evidence 5d5980896e

A recent line of work revealed Aβ-promoting function of PICALM by demonstrating that PICALM depletion decreased Aβ generation through disrupting clathrin-mediated endocytosis and internalization of γ-secretase [99,100].

Evidence 513507cda2

PICALM may also promote amyloid clearance from the brain by internalizing Aβ into endothelial cells and ultimately into to the bloodstream [101]

Evidence b929d4af10

Multiple large-scale GWAS demonstrate that variants of PICALM (phosphatidylinositol-L-binding clathrin assembly protein involved in endocytosis) are significantly associated with AD [90,93,94].

Evidence 880d998a68

PSEN1 M146L and A246E mutant cortical neurons have been shown to possess decreased activation of the CLEAR (coordinated lysosomal expression and regulation) gene network, as measured by a TFEB-driven luciferase assay, consistent with a reduction in autophagic activity [131].

Evidence ef22658b57

In a similar vein, PSEN1 A246E mutant cortical neurons have reduced mitophagy compared to control neurons, which is associated more with decreased lysosomal function rather than mitochondrial targeting [132].

Evidence 164b572dca

Evidence that p62 facilitates tau degradation has been demonstrated in several studies where p62 colocalized with tau in NFTs from AD patients [53].

Evidence 5b4c993051

For example, Babu et al. has shown that p62−/− knockout mice have increased levels of hyperphosphorylated tau, reduction of synaptophysin and changes in short term memory compared to p62+/− [54]

Evidence aaeae1dac4

Another common proteinopathy occurs from the misfolding of TARDNA binding protein 43 kDa (TDP-43), which is primarily seen in amyotrophic lateral sclerosis (ALS) and FTD [67]

Evidence 1cdd6d7ac8

TFEB at normal state is phosphorylated by mTOR complex 1, which inhibits its activity

Evidence 8de3177086

Recent work by Ulland et al. has also discovered an additional function of TREM2 in the maintenance of microglial macroautophagy and metabolism

Evidence f934797a01

TREM2 deficiency in an AD mouse model results in suppressed metabolic function in microglia through the dampening of the mTOR signaling pathway, which subsequently elicits a compensatory autophagic response to address the metabolic defect [109].

Evidence edca721eaa

Variants of TREM2 have been found to increase the risk of developing AD by approximately three times [105,106], further validating it as a risk factor for AD.

Evidence 3bfa4f0992

VPS35 mutations have been shown to disrupt macroautophagy [113] and mitochondrial function [114] and are associated with AD and PD [102,115].

Evidence c5a07a910d

Accumulation of misfolded proteins and damaged organelles is highly detrimental for neuronal homeostasis and survival.

Evidence e960bfb995

Altogether, as with proteinopathy, accumulation of damaged or dysfunctional mitochondria is detrimental to the development of AD pathologies

Evidence be7c6efd5e

Dysfunctional mitochondria are critically harmful to cells, as this leads to decreased synthesis of cellular ATP and accumulation of ROS, which further overburden and damage other functional mitochondria.

Evidence 04a57c4c04

Previous studies demonstrate impaired mitochondrial function preceding the accumulation of hallmark proteins in AD, such as Aβ [123,124] and tau [125].

Evidence bc56cc0546

Thus, as a quality control mechanism, mitophagy − a form of selective macroautophagy that specifically targets mitochondria − occurs in response to damaged or dysfunctional mitochondria in order to prevent mitochondrial bioenergetic deficits.

Evidence 3124399e7b

Recently, a comprehensive investigation utilizing gene expression analysis of the hippocampal region (CA1) of patients with Alzheimer’s disease identified that autophagosome formation and lysosomal biogenesis genes were upregulated at early stages of AD [21]

Evidence 9537ae54b6

A recent study reported that mitophagy is robustly induced in AD brains and in vitro models of mutant APP, accompanied with abnormal accumulation of depoloarized mitochondria [126]

Evidence 820a682edb

Formation of amyloid β (Aβ) plaques is one of the most notable hallmarks in AD pathology [30]

Evidence 14a87746a2

Cytosolic lipids are stored as triglycerides in lipid droplets and are hydrolyzed into fatty acid for energy under nutrient starvation


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