Given the size of AD-related proteins, mono- meric Aβ1-40, Aβ1-42 and tau, should be able to pass freely through astrocytic endfeet clefts at the glial barrier.72
In addition, insulin-degrading enzyme has been proposed to have a role in Aβ clearance through the BBB, which might explain why BBB clearance is sensitive to insulin.144
Aβ is cleared along perivascular drainage pathways.83 In both AD44,160 and CAA44 (commonly associated with AD84), perivascular drainage of Aβ is impaired.
In the early 2000s, mouse studies demonstrated that the majority (75%) of extracellular Aβ (eAβ) is cleared by the BBB, with only a minority (10%) being cleared by ISF bulk flow.
Third, ApoE4 is also associated with lower antioxidant activity than other ApoE isoforms,154,155 and it mediates BBB breakdown through a proinflammatory pathway involving cyclophilin A in pericytes.
The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI.
Specifically, ISF Aβ can be taken up by microglia and astrocytes, whereas perivascular Aβ can be degraded by vascular smooth muscle cells, perivascular macrophages, and astrocytes
Extracellular degradation of ISF proteins mainly consists of degradation by proteases expressed and secreted by cells such as astrocytes
Second, both Aβ and insulin are ligands that compete for degradation by insulin-degrading enzyme; thus, hyper- insulinaemia can reduce clearance of Aβ, which might partly explain the link between type 2 diabetes mellitus and AD.
Soluble Aβ can be removed from the brain by various clearance systems, including enzymatic degradation and cellular uptake, transport across the blood–brain barrier (BBB) and blood–cerebrospinal fluid barrier (BCSFB), interstitial fluid (ISF) bulk flow, and cerebro- spinal fluid (CSF) absorption into the circulatory and lymphatic systems.
Intracellular degradation of proteins occurs via the ubiquitin– proteasome pathway, the autophagy–lysosome pathway, and the endosome–lysosome pathway.56
These findings are in line with evidence suggesting that increased oxi- dative stress157 and loss of vascular integrity contribute to ageing158 and AD,159 as demonstrated by accelerated breakdown of the BBB and the neurovascular unit.
When characterized by autosomal dominant inheritance, EOAD is related to mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) or amyloid precursor protein (APP) genes.
ecifically, Aβ accumulation into extracellular plaques is marked by decreased CSF levels of Aβ1–42, and tau accumulation into NFTs is marked by increased CSF levels of total tau and hyperphosphory- lated tau.
The strongest identified genetic risk factor for LOAD is the apolipoprotein E (APOE) ε4 allele (APOE*ε4),
The pres- ence of ApoE4 is associated with reduced perivascular drainage of Aβ,161 which in turn is linked to deposition of immune complexes.
These findings support the link between TBI and tau aggre- gation, with resulting neurodegeneration similar to that seen in AD and chronic traumatic encephalopathy
Clearance of Aβ through the BBB is also medi- ated by α2-macroglobulin (α2M),14 and LDLR-related protein 2 (LRP2, also known as megalin) when LRP2 forms a complex with clusterin (also known as ApoJ).
The main ABC transporter responsible for Aβ efflux is ABCB1 (also known as P-glycoprotein 1 or MDR1),which directly exports Aβ into the circulation.
The main ABC transporter responsible for Aβ efflux is ABCB1 (also known as P-glycoprotein 1 or MDR1), which directly exports Aβ into the circulation.
In AD, these factors are impaired in a number of ways. First, expression of the blood efflux transporters LRP1123 and ABCB1147 is decreased, whereas expression of the blood influx transporter RAGE is upregulated.
Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme.
Free Aβ can be transported from the circulation into the interstitium via RAGE (advanced glycosylation end product-specific receptor).
which is located on the abluminal side of the brain endo- thelium,140 does not directly bind and extrude Aβ,141 but mediates Aβ clearance in an ApoE-dependent manner.
ApoE is a cholesterol transporter that competes with Aβ for efflux by LRP1 from the interstitium into the circula- tion;
competition for shared receptors is the primary mechanism by which ApoE mediates Aβ clearance
However, two-photon imaging studies from the past few years have suggested that ISF bulk flow—facilitated by astroglial aquaporin-4 (AQP4) channels and named the glymphatic (glial + lymphatic) system—contributes to a larger portion of eAβ clearance than previously thought.
If APP is first cleaved by β-secretase 1 (also known as BACE1) instead of α-secretase, the subsequent γ-secretase cleavage will result in soluble monomeric Aβ.
although genome-wide association studies have linked LOAD to several other genetic variants, such as TREM2 (triggering receptor expressed on myeloid cells 2),27 clusterin (CLU),28 and phosphatidylinositol-binding clathrin assembly protein (PICALM).28,29
Some evidence suggests that LRP1 is the main transporter for Aβ efflux at the BBB, whereas other studies have demonstrated its role to be quite minor.
Specifically, local soluble Aβ is transferred from the interstitium to the brain by LDL receptor (LDLR) family members such as LRP1, and ATP-binding cassette transporters (ABC transporters).
Phosphorylation of tau by protein kinase A increases its resistance to degradation by calpain
APP is cleaved by α-secretase, which precludes forma- tion of Aβ, and the resulting carboxy-terminal fragment is then cleaved by γ-secretase.103 The resulting products do not aggregate.104
Intracellular Aβ (iAβ) can be degraded by proteasomes via the ubiquitin–proteasome pathway in neurons,116 lyso- somal cathepsin enzymes,117 proteases (such as insulin- degrading enzyme, a thiol metalloendopeptidase that degrades monomeric Aβ) and insulin.
Tau is mainly cleared through intracellular degrada- tion by lysosomes via the autophagy–lysosome pathway, and by proteasomes via the ubiquitin–proteasome pathway.202
Recent mouse studies suggest that the AQP4-dependent glymphatic pathway is an important clearance system for driving the removal of soluble Aβ from the interstitium.
Of note, a high-fat prenatal maternal diet has recently been reported to result in a failure of Aβ clearance along cerebrovascular basement membranes.
Emerging evidence suggests that Aβ clearance is impaired in both early-onset and late-onset forms of AD.
Various factors have been reported to positively and negatively modulate the risk of LOAD. Specifically, the greatest overall risk factor for LOAD is ageing;
Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD
Recent advances now enable several AD-related brain changes to be detected in vivo: 18F-FDG-PET detects decreases in glucose metabolism,45,46 and MRI detects brain atrophy, as well as diffusion and perfu- sion abnormalities, which are most prominent in the vul- nerable hippocampal formation and cortical regions.
First, expression of neprilysin is decreased in AD,126 especially in regions with high Aβ loads such as the hippocampus and temporal gyrus.127
Although overall matrix metallo- proteinase 2 expression is increased in AD,58 its activity is reduced in astrocytes that surround Aβ plaques.
In AD, the choroid plexus undergoes many structural changes, such as calcification, fibrosis and Aβ deposition, all of which can obstruct CSF production.
These findings might partly explain why sleep impairment increases the risk of AD
First, in ageing, and particularly in AD, CSF production by the choroid plexus is reduced, as shown by decreased water secretion into the ventricles via AQP1 water channels.
Inflammation, a common feature of AD, can affect ligand affinity by making the pH more acidic, which promotes hyperphosphorylation of tau and induces conforma- tional changes in Aβ that hinder its clearance.
Thus, sleep could indirectly increase BBB clearance of Aβ through increased glymphatic bulk flow, but it might also directly increase clearance through the BBB via various mechanisms, such as molecular changes (for example, upregulated LRP1), as seen with AD-protective physical and cognitive activity in mice.1
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