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)
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)
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)
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)
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)
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)
Trehalose also can reduce Aβ levels in hippocampus (Du et al. 2013)
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
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)
Meanwhile, an animal experiment showed that IDE expression will descend with age and diabetes, then resulting in Aβ deposition (Kochkina et al. 2015)
Among MMPs, MMP-2, -3 and -9, stimulated by Aβ, play important roles in degrading Aβ (Wang et al. 2014)
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)
In addition, Aβ deposition in CP also blocks CSF production in AD (Serot et al. 2012).
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
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)
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)
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).
A recent study showed that omega-3 polyunsaturated fatty acids also increase Aβ degradation by proteases
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)
Simvastatin and atorvastatin enhance extracellular Aβ degradation via increasing NEP secretion from astrocytes by activating MAPK/Erk1/2 (Yamamoto et al. 2016)
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)
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)
Minocycline not only suppresses pro-inflammatory phenotypes of microglia but also promotes their phagocytic clearance of Aβ (El-Shimy et al.2015)
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)
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)
Moreover, pioglitazone seems to be an effective therapeutic approach targeting Aβ clearance via similar mechanisms to those of rosiglitazone (Mandrekar-Colucci et al. 2012)
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)
Somatotatin also up-regulates the expression and secretion of IDE in order to enhance Aβ clearance (Tundo et al.2012)
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
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)
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)
Recent evidence has indicated that autophagy is damaged in astrocytes accompanied by the expression of APOE4, which attenuates Aβ degradation (Simonovitch et al. 2016)
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)
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)
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)
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)
CSF is produced mainly by choroid plexus
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)
A study suggested that Aβ is removed from CSF to cervical lymph nodes via perineural space of the olfactory nerve (Picken 2001; Pollay 2010)
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)
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
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)
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)
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)
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)
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
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
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
Microglial cells, the key immune cells of the brain, play an important part in the phagocytosis of Aβ
Tenuigenin could obviously reduce intracerebral Aβ1–40 accumulation in AD mouse brain by increasing the content of 26S proteasome (Chen et al. 2015)
Intracellular protein degradation is performed by UPS and ALS (Wong and Cuervo 2010
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)
Intracellular Aβ degradation pathways mainly contain two major pathways: UPS and ALS (Vilchez et al. 2014)
In addition, there is accumulating evidence to prove that Aβ can be cleared by ALS.
On the one hand, it is beneficial to the clearance of tau aggregates
On the other hand, it brings about tau fragmentation into pro-aggregating forms due to the failure of F1 to enter the lysosome
It has been indicated that intracellular tau proteins are also degraded by autophagy and proteasomal pathways (Wang and Mandelkow 2012)
Dysfunction of UPS brings about the deposition of hyperphosphorylated tau oligomers in synapses (Tai et al. 2012)
Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats
In addition, triggering receptor expressed on myeloid cells 2 (TREM2), ATP-binding cassette transporter A7, and CD33 also play key roles in microglial phagocytosis
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)
The proteolytic degradation is also a major pathway of Aβ clearance
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
And autophagy-lysosomal activity is induced via two signal pathways: mammalian target of rapamycin (mTOR)-dependent pathway and mTORindependent pathway (Tan et al. 2014b)
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
Fractalkine can keep microglia in the right state via interacting with CX3CR, thus contributing to Aβ clearance
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)
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
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)
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)
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)
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)
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)
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)
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
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)
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
In addition, the luminal residing receptor for advanced glycation end products (RAGE) is an Aβ influx transporter (Deane et al. 2003)
Anti-inflammatory mediator annexin A1 (ANXA1) can reduce Aβ content by increasing its degradation by NEP (Ries et al. 2016)
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)
Unfortunately, the glymphatic system may be impaired due to the loss of AQP4 after traumatic brain injury (Iliff et al. 2014)
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)
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)
IDE, a zinc endopeptidase, can degrade extracellular Aβ (Vekrellis et al. 2000)
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)
GLUT1, glucose transporter expressed in the BBB, regulates LRP1-dependent Aβ clearance via increasing the expression of LRP1
Tau proteins, microtubule-associated proteins, take part in the formation of microtubules for the sake of maintaining the stability of microtubules
NEP, plasma membrane glycoprotein, is a zinc metalloendopeptidase and the most efficient hydrolytic enzyme in degrading Aβ in vitro (Shirotani et al. 2001)
And in APP transgenic mice, long-term gene therapy of NEP ameliorates behavior by lowering the levels of Aβ (Spencer et al. 2008)
PICALM, mainly expressed in endothelial cells of vascular walls, contributes to the transport of Aβ across the BBB into blood (Xu et al. 2015)
And in AD, the decreasing expression of PICALM in brain endothelium reduces Aβ clearance (Zhao et al. 2015b)
Protein phosphatase 2A agonists are reported to activate autophagy by affecting AMPK and mTORC1 signaling pathways (Magnaudeix et al. 2013)
Brain plasmin degrades Aβ
However, the levels and activity of plasmin are reduced in AD brains (Ledesma et al. 2000)
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)
Transcriptional factor EB downregulates Aβ levels by affecting autophagy-lysosome (Zhang and Zhao 2015)
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)
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)
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)
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)
However, their dysfunction in AD due to some factors will reduce Aβ clearance
After traumatic brain injury (TBI), the expression and location of AQP4 will change, inducing its dysfunction (Ren et al. 2013)
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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