PubMed: 29626319

Clearance of Amyloid Beta and Tau in Alzheimer's Disease: from Mechanisms to Therapy.
Neurotoxicity research
Tan L | Yu JT | Cao X | Xin SH

Evidence b5eabae802

Monocytes in peripheral blood have been demonstrated to play an important role in clearing Aβ that diffuses from brain to blood (Halle et al. 2015)

Evidence 11633a5340

Epigallocatechin-3-gallate enhances the clearance of ADrelevant phosphorylated tau species via increasing mRNA expression of autophagy adaptor proteins NDP52 and p62 (Chesser et al. 2016)

Evidence 6faa9f33a8

Impairment of 26S proteasome induced by tau can be prevented early in disease through activation of cAMP-PKA signaling, and raising the levels of cAMP with rolipram may enhance tau degradation (Myeku et al. 2016)

Evidence 356f22cac1

For example, eicosapentaenoic acid (EPA) can induce the activity of IDE and increase its gene expression, and docosahexaenoic acid (DHA) also directly elevates IDE activity and affects sorting by boosting exosome release of IDE (Grimm et al. 2016)

Evidence f55f2e6eb3

Recent acknowledged drugs can improve autophagy by acting on the process of autophagy-lysosome formation and then increasing tau clearance, such as methylene blue, lithium, and trehalose (Congdon et al. 2012; Kruger et al. 2012; Shimada et al. 2012)

Evidence fe79505475

Proteasome inhibitors and trehalose increase autophagy and decrease tau content by up-regulating the expression of cochaperone BAG3 targeting tau to the autophagy pathway for degradation (Lei et al. 2015)

Evidence 8ae3bd3aa2

Trehalose also can reduce Aβ levels in hippocampus (Du et al. 2013)

Evidence e38da704b7

In addition, Aβ1–42 can increase the expression of TREM2, a surface signaling receptor in microglia, and the up-regulation of TRME2 can facilitate microglial phagocytosis of Aβ1–42

Evidence 58957b06af

The excessive deposition of Aβ also induces oxidative stress and mitochondrial dysfunction, which fails to offer ATP for the degradation of targeted proteins by UPS in yeast (Chen and Petranovic 2015)

Evidence ce9d1566e5

Meanwhile, an animal experiment showed that IDE expression will descend with age and diabetes, then resulting in Aβ deposition (Kochkina et al. 2015)

Evidence 104ca920a3

Among MMPs, MMP-2, -3 and -9, stimulated by Aβ, play important roles in degrading Aβ (Wang et al. 2014)

Evidence 688fa67260

By collecting time-matched blood samples from cerebral vein, femoral vein, and radial artery in patients to measure the concentration of Aβ for every blood sample and figure out the turnover of it from vein to artery, it has been shown that transport of Aβ from brain to blood via the BBB and CSF absorption accounts for half of the total clearance of Aβ in CNS in humans, and furthermore, the clearance rate of Aβ via the BBB and CSF absorption accounts for the same proportion (Roberts et al. 2014)

Evidence f3d47c3b59

In addition, Aβ deposition in CP also blocks CSF production in AD (Serot et al. 2012).

Evidence 47331a9112

In addition, Jeffrey J. Iliff et al. have demonstrated that the Aβ in brain interstitium can be eliminated from the parenchyma by the bulk flow of interstitial fluid, which also depends on a water channel aquaporin-4 (AQP4) expressed in astrocyte endfeet

Evidence 3322759d74

It has been discovered that cromolyn sodium, already used in the cure for asthma, can enter the central nervous system and promote Aβ monomer clearance by microglial phagocytosis (Hori et al. 2015)

Evidence 0b27559007

Dietary pre-administration of docosahexaenoic acid prevents RBCs from oxidative damage due to its antioxidative characteristic and also increases Aβ degradation by RBC in a lipid raft-dependent manner (Hashimoto et al. 2015)

Evidence d64987f52b

And ginsenoside Rg1 and granulocyte-colony stimulating factor may up-regulate activities of NEP in retinal cells in an AD mouse model to reduce tau protein pathology (He et al. 2014) (Doi et al.2014).

Evidence 4063c3db1a

A recent study showed that omega-3 polyunsaturated fatty acids also increase Aβ degradation by proteases

Evidence 64ae548860

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015)

Evidence cfd4aab3e6

Simvastatin and atorvastatin enhance extracellular Aβ degradation via increasing NEP secretion from astrocytes by activating MAPK/Erk1/2 (Yamamoto et al. 2016)

Evidence cd2d66d502

1,25(OH)2D3, the active form of vitamin D, plays a key role in enhancing transport of Aβ1–40 from the brain to the blood by reducing RAGE levels at the BBB, and also in contributing to periphery clearance by increasing levels of LRP1 both in vivo and in vitro (Guo et al. 2016b)

Evidence 003560a97f

Cholinesterase inhibitors donepezil and rivastigmine, upregulating transport proteins P-glycoprotein and LRP1, may improve Aβ clearance in the liver of rats (Mohamed et al. 2015)

Evidence 1cf1774345

Minocycline not only suppresses pro-inflammatory phenotypes of microglia but also promotes their phagocytic clearance of Aβ (El-Shimy et al.2015)

Evidence 68a13839ea

Nobiletin, a flavone from citrus depressa, leads to gene expression and improves the protein level and activity of NEP in SK-N-SH cells, thus reducing Aβ levels (Fujiwara et al. 2014)

Evidence aa318443c9

Oleocanthal, a special component of extra-virgin olive oil, increases cerebral clearance of Aβ across the BBB by enhancing the expression of important efflux transport proteins at the BBB containing LRP1 and P-gp, and activating the APOE-dependent Aβ clearance pathway in mice brains (Qosa et al. 2015)

Evidence a021c1eb99

Moreover, pioglitazone seems to be an effective therapeutic approach targeting Aβ clearance via similar mechanisms to those of rosiglitazone (Mandrekar-Colucci et al. 2012)

Evidence 094124b887

Rosiglitazone, a highaffinity agonist for PPARγ, can clear Aβ by activating microglia and promoting its phagocytosis via increasing the levels of CD36, a receptor expressed in it (Escribano et al. 2010)

Evidence f4b4babf41

Somatotatin also up-regulates the expression and secretion of IDE in order to enhance Aβ clearance (Tundo et al.2012)

Evidence 581a66b605

Statin can lead to extracellular IDE secretion from astrocytes in an autophagy-based unconventional secretory pathway (Glebov and Walter 2012), thus enhancing the extracellular removal of Aβ

Evidence bec60f59f9

In a similar manner, a recent experiment indicated that water influx into the CSF is significantly reduced in AD-patients, which may impair Aβ clearance (Suzuki et al. 2015)

Evidence 2ece17008e

In addition, studies have shown that the 20S proteasome can play a key role in digesting proteins directly via an ATP-independent and ubiquitin-independent pathway (Jariel-Encontre et al. 2008)

Evidence c54a1741d8

Recent evidence has indicated that autophagy is damaged in astrocytes accompanied by the expression of APOE4, which attenuates Aβ degradation (Simonovitch et al. 2016)

Evidence 10ea6e2573

The expression of APOE ε4 allele is related to the reduction of Aβ clearance from the brain by impairing its arterial perivascular drainage, accompanied by changes of protein levels in cerebrovascular basement membrane (Hawkes et al. 2012)

Evidence 47d16de137

There is a study showing that the BCSFB is the primary removal channel compared with arachnoid villi, resulting from the receptor LRP1 expressed in epithelial cells of choroid plexus in the BCSFB (Fujiyoshi et al. 2011)

Evidence 53c2eaf5c3

In the meanwhile, a study supported this idea that AQP4 deficiency can reduce the rate of Aβ clearance via glymphatic pathway (Iliff and Nedergaard 2013)

Evidence fdcb20034b

It has been reported that ISF tau can be eliminated by the glymphatic system and the function of this clearance mechanism may be impaired due to the loss of AQP4 after TBI, which ultimately accelerates tau accumulation (Iliff et al.2014)

Evidence f7b99b330b

CSF is produced mainly by choroid plexus

Evidence b4cfcab6e1

By measuring Aβ levels in superior vena cava and inferior vena cava, it is clear thatAβ levels are getting lower and lower along the direction of the vein blood flow, and the contents of Aβ40 and total Aβ in artery are significantly less than those in vein, suggesting a part of Aβ40 and total Aβ can be cleared by peripheral organs and tissues, such as the liver, kidney, skin, and the gastrointestinal tract, although there is no change in Aβ42 concentrations (Xiang et al. 2015)

Evidence 8972603321

A study suggested that Aβ is removed from CSF to cervical lymph nodes via perineural space of the olfactory nerve (Picken 2001; Pollay 2010)

Evidence ee34d1c78d

Aβ is cleared by receptor-mediated microglial phagocytosis and degradation, such as scavenger receptors, chemokine-like receptor 1, toll-like receptors, and G protein-coupled receptors including formyl peptide receptor 2 (Yu and Ye 2015)

Evidence 981954f327

However, some proteins fail to be transported out of the brain through intercellular tight junctions, and can only be transported into blood by transporters expressed in the capillary endothelium

Evidence 17fe17da65

Under physiological conditions, UPS, located in the cytosol and the nucleus in eukaryotic cells, as a major intracellular short-lived protein degradation system (Schwartz and Ciechanover 2009), mediates the clearance of misfolded or other abnormally modified proteins with the help of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), ubiquitin ligase (E3), and the 26S proteasome for the sake of preventing the accumulation of toxic substances (Shang and Taylor 2011)

Evidence f38fe037a9

Human brain tau can be degraded by the proteases, such as cathepsin-D, amino peptidases, human high temperature requirement serine protease A1 (HTRA1), thrombin, caspases, and calpains (Chesser et al. 2013; Kenessey et al. 1997)

Evidence 05467fad85

Aβ in periphery is mainly cleared by blood components, such as red cells (RBCs) and monocytes, or some tissues and organs, such as the liver and kidney (Fig. 2)

Evidence 4e2b17b815

Among these peripheral organs and tissues mentioned above, the liver and kidney are considered to be the major organs for the clearance of Aβ in periphery (Ghiso et al. 2004)

Evidence bf20d4068f

Microglia, one type of glial cells, the equivalent of the macrophages that exist in the brain and spinal cord, is the first and also the main line of immune defense in CNS

Evidence 6c9121da97

Activated microglia has a double effect on AD progression (Li et al. 2014). On the one hand, they can release some proinflammatory cytokines, stimulating inflammatory response and ultimately leading to neuronal injuries and death

Evidence 9546a645d9

On the other hand, they may show beneficial effects via facilitating aberrant protein clearance by means of microglial migration to the damaged, aberrant area, and phagocytosis of unnecessary materials in the early stages of AD

Evidence e831774384

Microglial cells, the key immune cells of the brain, play an important part in the phagocytosis of Aβ

Evidence 11d8113af4

Tenuigenin could obviously reduce intracerebral Aβ1–40 accumulation in AD mouse brain by increasing the content of 26S proteasome (Chen et al. 2015)

Evidence db69aaa859

Intracellular protein degradation is performed by UPS and ALS (Wong and Cuervo 2010

Evidence 5d93dd6a0c

Intracellular Aβ clearance can be achieved through UPS and ALS, and extracellular Aβ is degraded by glial phagocytosis, such as microglia, astrocytes, and proteases from neurons and astrocytes (Fig. 2)

Evidence d7a9c8eadb

Intracellular Aβ degradation pathways mainly contain two major pathways: UPS and ALS (Vilchez et al. 2014)

Evidence 7912b0e633

In addition, there is accumulating evidence to prove that Aβ can be cleared by ALS.

Evidence 0aed8508bc

On the one hand, it is beneficial to the clearance of tau aggregates

Evidence d090e45583

On the other hand, it brings about tau fragmentation into pro-aggregating forms due to the failure of F1 to enter the lysosome

Evidence d8047753a0

It has been indicated that intracellular tau proteins are also degraded by autophagy and proteasomal pathways (Wang and Mandelkow 2012)

Evidence 490357bb47

Dysfunction of UPS brings about the deposition of hyperphosphorylated tau oligomers in synapses (Tai et al. 2012)

Evidence 6b5d1b6da7

Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats

Evidence f9082b5958

In addition, triggering receptor expressed on myeloid cells 2 (TREM2), ATP-binding cassette transporter A7, and CD33 also play key roles in microglial phagocytosis

Evidence f14b57d3b6

There was direct evidence to show that microglial phagocytosis plays a pivotal role in clearance of tau in vitro and in vivo (Bolos et al. 2015)

Evidence b41a4b3173

The proteolytic degradation is also a major pathway of Aβ clearance

Evidence c13ffe739b

Under normal conditions, Aβ production in brain parenchyma results from hydrolyzing amyloid precursor proteins via beta-secreted enzymes and gamma-secreted enzymes, and the most common subtypes of Aβ in human body are Aβ1–40 and Aβ1–42

Evidence 429590f419

And autophagy-lysosomal activity is induced via two signal pathways: mammalian target of rapamycin (mTOR)-dependent pathway and mTORindependent pathway (Tan et al. 2014b)

Evidence 34f332cddb

Moreover, researchers reported that TTR, a transporter protein mainly synthesized in the CP of the brain and secreted into the CSF, can reduce the Aβ contents in brain (Ribeiro et al. 2014), which gives us inspiration that TTR bound to Aβ may be a natural mechanism of brain Aβ clearance

Evidence b0fdb12a88

Fractalkine can keep microglia in the right state via interacting with CX3CR, thus contributing to Aβ clearance

Evidence c724029c2a

It is known that RBCs can facilitate Aβ clearance relying on complement C3b-dependent adherence to complement receptor 1(CR1) on RBCs (Rogers et al. 2006)

Evidence a51d18c932

In addition, a recent experiment showed that a great deal of Aβ in the blood circulation may combine with serum albumin (Stanyon and Viles 2012), which provided a novel clearance pathway in periphery

Evidence 556d46da05

However, there was a study indicating that calpain-mediated tau cleavage can result in the generation of tau fragments, which may possess neurotoxicity in AD (Ferreira and Bigio 2011)

Evidence 5cfcb1e4b5

Exercise training can increase extracellular Aβ clearance in the brains of Tg2576 mice in a dose-dependent manner through up-regulating NEP, IDE, MMP9, LRP1, and HSP70 (Moore et al. 2016)

Evidence c42251eba8

Extracellular Aβ degrading enzymes include neprilysin (NEP), insulin-degrading enzyme (IDE), matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), endothelin-converting enzyme (ECE), and plasmin (Baranello et al. 2015)

Evidence f4f11836d4

A recent study has shown that ABCA7, mainly expressed in human microglial cells, also regulates microglial phagocytic function and decreases Aβ deposition (Zhao et al. 2015a)

Evidence 875866e7b7

However, current evidence showed that ATP-binding cassette transporter A7 deficit can increase Aβ deposition in brain by promoting Aβ-production through increasing β-secretase 1 levels rather than influencing the clearance of Aβ in APP/PS1 mice (Sakae et al. 2016)

Evidence d3983fa5c8

And meanwhile, P-glycoprotein (Pgp), as an efflux transporter, highly expressed on the lumen surface of the BBB, has been proven to transport Aβ out of brain (van Assema et al. 2012; Wei et al. 2016)

Evidence f237b0368f

However, recently, it has been reported that the expression and transport activity of P-gp are impaired in sporadic AD as a result of its ubiquitination, internalization, and proteasome-dependent degradation derived from Aβ40 (Chiu et al. 2015; Hartz et al. 2016), which will result in Aβ deposition

Evidence 77f59adb0f

In addition, ACE expression also enhances Aβ clearance, and the levels and activity of ACE are elevated in AD brains (Barnes et al. 1991; Hemming and Selkoe 2005)

Evidence 8407b22bfe

ACE, a membrane-bound zinc metalloprotease, catalyzes the transformation of angiotensin I to angiotensin II, which is beneficial to the maintenance of body fluid, blood pressure, and sodium balance

Evidence beda49badf

In addition, the luminal residing receptor for advanced glycation end products (RAGE) is an Aβ influx transporter (Deane et al. 2003)

Evidence 38b6ff801a

Anti-inflammatory mediator annexin A1 (ANXA1) can reduce Aβ content by increasing its degradation by NEP (Ries et al. 2016)

Evidence a21b8d3862

It has been shown that choroid plexus dysfunction, due to the reductive expression of epithelial aquaporin-1, a water channel protein, can induce CSF production, which in turn damages Aβ clearance in a triple transgenic mouse model of AD (Gonzalez-Marrero et al. 2015)

Evidence eeb2d0f04a

Unfortunately, the glymphatic system may be impaired due to the loss of AQP4 after traumatic brain injury (Iliff et al. 2014)

Evidence d9a3653fe0

Consistent with the conclusion above, there is evidence that glymphatic drainage of ISF bulk flow relying on water channel AQP4 can decrease the levels of Aβ in brain (Iliff et al. 2012)

Evidence 5e5916735c

Besides, CD33, most abundantly expressed in microglia in AD, inhibits normal function of immune cells and impairs microglia-mediated clearance of Aβ (Jiang et al. 2014b)

Evidence e703634fad

IDE, a zinc endopeptidase, can degrade extracellular Aβ (Vekrellis et al. 2000)

Evidence ad3588e4bc

LRP1, efflux transporter protein, is expressed mainly at the abluminal membrane of the BBB and highly expressive LRP1 can elevate the rate of Aβ clearance from brain to blood (Pflanzner et al. 2011)

Evidence 2f01ea7e8d

GLUT1, glucose transporter expressed in the BBB, regulates LRP1-dependent Aβ clearance via increasing the expression of LRP1

Evidence 5be17ad558

Tau proteins, microtubule-associated proteins, take part in the formation of microtubules for the sake of maintaining the stability of microtubules

Evidence d7953bae65

NEP, plasma membrane glycoprotein, is a zinc metalloendopeptidase and the most efficient hydrolytic enzyme in degrading Aβ in vitro (Shirotani et al. 2001)

Evidence 1a523920ba

And in APP transgenic mice, long-term gene therapy of NEP ameliorates behavior by lowering the levels of Aβ (Spencer et al. 2008)

Evidence 45a975387b

PICALM, mainly expressed in endothelial cells of vascular walls, contributes to the transport of Aβ across the BBB into blood (Xu et al. 2015)

Evidence 321e4f2307

And in AD, the decreasing expression of PICALM in brain endothelium reduces Aβ clearance (Zhao et al. 2015b)

Evidence 5d969c7d42

Protein phosphatase 2A agonists are reported to activate autophagy by affecting AMPK and mTORC1 signaling pathways (Magnaudeix et al. 2013)

Evidence f76bd2dab6

Brain plasmin degrades Aβ

Evidence 260b5a4439

However, the levels and activity of plasmin are reduced in AD brains (Ledesma et al. 2000)

Evidence b54a25a519

In addition, the transport of GLUT1-mediated glucose into the brain is also beneficial to maintaining the integrity of the BBB, thereby ensuring the normal transport of Aβ from brain into blood (Winkler et al. 2015)

Evidence 85cf553d29

Transcriptional factor EB downregulates Aβ levels by affecting autophagy-lysosome (Zhang and Zhao 2015)

Evidence 4d1020fab5

Xiao et al. have also obtained the consistent conclusion that transcriptional factor EB, a master regulator of lysosome biogenesis, improves lysosomal function in astrocytes, which may promote Aβ clearance and attenuate plaque pathogenesis (Xiao et al. 2014)

Evidence 33cc1216c2

For example, like Aβ, clearance of pTau/NFT also can be regulated by TFEB, which increases the activity of autophagy and lysosome (Polito et al. 2014)

Evidence 6fb059dab9

However, due to the presence of the R47H mutation in AD, TREM2 cannot effectively recognize the lipid ligands and then fails to activate microglia, which leads to Aβ deposition (Jiang et al. 2014a; Jiang et al. 2013)

Evidence ab542add1b

As is known, the accumulation of frameshift ubiquitin-B (UBB) mutant protein UBB (+1) can block the 26S proteasome in cell lines, and then can reduce Aβ clearance (Hope et al. 2003)

Evidence a6bf8c536d

However, their dysfunction in AD due to some factors will reduce Aβ clearance

Evidence baa4eae92d

After traumatic brain injury (TBI), the expression and location of AQP4 will change, inducing its dysfunction (Ren et al. 2013)

Evidence 8ab40a8329

Later, an experiment on live mice using some special methods has also proved that natural sleep or sleep resulting from anesthesia can increase interstitial space by 60%, thereby speeding up the exchange of CSF-ISF and finally increasing the elimination of Aβ (Xie et al. 2013)


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