PubMed: 22908190

The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease.
Cold Spring Harbor perspectives in medicine
Ihara Y | Morishima-Kawashima M | Nixon R

Evidence ad31e2ea05

It has been reported that tau is degraded by several major cellular degradation systems, including calpain, caspases, lysosomes, and proteasomes.

Evidence a4fccf9acf

By up-regulating endocytosis, high dietary LDL-cholesterol and overexpression of its receptor ApoE (particularly ApoE 14) elevate bCTF levels and increase delivery of Ab1–42 to lysosomes in cellular model systems (Ji et al. 2006; Cossec et al. 2010).

Evidence 8a0a861c9b

Consistent with these findings, strong overexpression of human Ab42, but not Ab40, in Drosophila neurons induces age-related accumulation of Ab in autolysosomes and neurotoxicity (Ling et al. 2009).

Evidence a9dd0caa89

Ab42-induced neurotoxicity is further enhanced by autophagy activation and is partially rescued by autophagy inhibition.

Evidence e3eff1b319

Moreover, administration of UCH-L1 can reverse the amyloid b-protein–induced synaptic dysfunction and memory loss in transgenic mice overexpressing APP and PS1 (Gong et al. 2006).

Evidence e62e60806e

Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo.

Evidence e87d5d6ca5

Endocytic pathway up-regulation in AD stemming in part from pathological rab 5 activation generates higher levels of Ab (Mathews et al. 2002; Grbovic et al. 2003) that must be cleared in part by lysosomes.

Evidence 66f828931b

Pathological rab5 activation, which in Down syndrome is dependent on bCTF generation (Jiang et al. 2010), can up-regulate endocytosis in a manner functionally equivalent to the elevated endocytosis associated with increased synaptic activity, which is considered a source of Ab generation (Cirrito et al. 2008).

Evidence 2679943d5f

Induction of autophagy is generally controlled by the mTOR kinase (mammalian Target of Rapamycin), which is regulated by growth factors (especially insulin) and nutrient levels.

Evidence fde0ed8feb

High dietary LDL-cholesterol and overexpression of its receptor ApoE (particularly ApoE 14) elevate bCTF levels (Ji et al. 2006; Cossec et al. 2010), and these levels are also elevated in NPC, DS, and AD, particularly in early-onset forms of AD caused by certain mutations of APP.

Evidence 3ad21a5114

In this regard, elevated bCTF levels induced by APP overexpression, elevated dietary cholesterol, or overexpression of its receptor ApoE (particularly ApoE 14) can upregulate endocytosis and enlarge endosomes (Laifenfeld et al. 2007; Chen et al. 2010; Cossec et al. 2010), leading to impaired endosome retrograde transport (S Kim and RA Nixon, unpubl.).

Evidence 71ecd92bb9

Bilateral injection of lactacystin, a specific proteasome inhibitor, into the CA1 region of the rat hippocampus blocks long-term memory formation (Lopez-Salon et al. 2001

Evidence 29de73c14d

It is this abnormal rab5 activation that causes protein and lipid accumulation in endosomes, slowed lysosomal degradation of endocytic cargoes,endosome swelling (Cataldo et al. 2008), and disrupted retrograde transport of endosomes (S Kim and RA Nixon, unpubl.).

Evidence 4d9d253c06

Accelerated endocytosis also increases protein and lipid accumulation in endosomes and slows lysosomal degradation of endocytic cargoes (Cataldo et al. 2008), leading to lysosomal instability and neurodegeneration, as discussed below.

Evidence e685fc001b

Chronic low-level stimulation of autophagy through peripheral administration of rapamycin or other agents (Tian et al. 2011), or enhancing lysosomal proteolysis selectively (Sun et al. 2008; Yang et al. 2011), can markedly diminish Ab levels and amyloid load in APP transgenic mice, underscoring the importance of lysosomal clearance of Ab.

Evidence ead9b64755

Consistent with these findings, rapamycin induction of autophagy reduces tau pathology in the triple transgenic AD-mouse model (Caccamo et al. 2010), whereas in other models, autophagic–lysosomal dysfunction amplifies tau pathology and tau neurotoxicity (Hamano et al. 2008; Khurana et al. 2010).

Evidence c82711f657

Peripheral administration of rapamycin to strongly stimulate autophagy substantially reduces amyloid deposition and tau pathology in both APPand triple transgenic mouse models of AD pathology (Caccamo et al. 2010; Spilman et al. 2010; Tian et al. 2011)

Evidence 4dd3d5f2af

We soon found that DF2 strongly stained cortical and brain stem Lewy bodies in brain sections from “diffuse Lewy body disease” (Kuzuhara et al. 1988), as originally described by Kenji Kosaka (1978), who proposed that some elderly subjects dying with dementia had many cortical Lewy bodies

Evidence c1f84436ee

The DF2 immunoreactivity of Lewy bodies led us to search for similar DF2-positive inclusions, and we found that Lewy-like bodies in motor neurons in amyotrophic lateral sclerosis (ALS; Murayama et al. 1990a) and Pick bodies in Pick’s disease (Murayama et al. 1990b) were strongly reactive; the latter stained also for tau, whereas the former stained neither for tau nor a-synuclein.

Evidence b3c02a0659

In this dementia, Lewy bodies are abundant in cortical neurons, especially in the cingulate gyrus, in addition to their presence in the substantia nigra and locus ceruleus, their prototypical loci in Parkinson’s disease.

Evidence 5ad9ed995b

Polyclonal antibodies to the classical paired helical filaments (PHFs) found in the neurofibrillary tangles and dystrophic neurites of AD were first raised in about 1982, allowing exploration of the component(s) of PHFs using immunochemical approaches (Ihara et al. 1983)

Evidence 681a58c35a

In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected.

Evidence 3bcc381ee5

That is, in areas where NFTs formed abundantly, including hippocampus and parahippocampal gyrus and superior and middle temporal gyri, proteasome activity (as assessed by chymortrypsinlike and postglutamyl peptidases) appeared to be most affected, whereas occipital gyri and cerebellum, which often have few or no NFTs, were least affected (Keller et al. 2000).

Evidence 3780a2a1dc

A proteomic analysis has shown down-regulation and oxidative modification of UCH-L1 in the AD brain, and the levels of soluble UCH-L1 were inversely proportional to the number of NFTs (Choi et al. 2004).

Evidence 5b2c4ca693

For example, immunocytochemistry showing the presence of K63- linked polyubiquitin in a fraction of the NFTs in AD cortex (Paine et al. 2009) suggests an active involvement of autophagy in the mechanism of AD.

Evidence 0975e951cb

Neurofibrillary tangles composed of tau proteins in a hyperphosphorylated state are rarely observed in abundance except in AD and a limited number of aging-related tauopathies.

Evidence 2191f91686

AV accumulations are not specific to the degenerative phenomena of AD; however, in AD brain, the extensive numbers of dystrophic neurites (Masliah et al. 1993; Schmidt et al. 1994), their characteristic marked distension, and the fact that they are predominantly filled with AVs distinguish the pattern and magnitude of this pathology from that of other aging-related neurodegenerative diseases (Benzing et al. 1993).

Evidence fa08231271

The profuse and selective accumulation of AVs in neurons in AD reflects a defect in the clearance of AVs by lysosomes rather than an abnormally elevated induction of autophagy

Evidence a129320a82

AVs and lysosomes constitute more than 95% of the organelles in dystrophic neuritic swellings in AD and AD mouse models, implying a cargo-specific defect in axonal transport, rather than a global one.

Evidence 2a92711bc9

AVs are also enriched in APP substrates and secretases and, during autophagy, Ab peptide is generated from APP (Yu et al. 2005), although it is subsequently degraded in lysosomes under normal circumstances (Heinrich et al. 1999; Bahr et al. 2002; Florez-McClure et al. 2007).

Evidence ac0cf6a531

During the initiation of endocytosis, the invagination of plasmamembranes into vesicles is mediated most often by the clathrin/adaptor protein complex, but also via caveolae or bulk macropinocytosis (Lim et al. 2011).

Evidence 585cc4a569

Beyond influencing Ab generation and toxicity, defective endosome functioning plays a crucial Ab-independent role in the failure of retrograde NGF signaling that leads to basal forebrain cholinergic neuron degeneration in the Ts65Dn mouse model of DS (Cooper et al. 2001; Delcroix et al. 2004).

Evidence ab6662ea41

It has recently become appreciated that ubiquitination of proteins by covalent modification tags them for elimination not only through the proteasome (the ubiquitin–proteasome system or UPS) but also through the lysosomal system.

Evidence cc173528cf

A continuum of pathological changes of the lysosomal network unfolds in neurons as Alzheimer disease progresses, including dysregulation of endocytosis, increased lysosome biogenesis and, later, progressive failure of lysosomal clearance mechanisms (Fig. 6; Nixon et al. 2006).

Evidence 1cd9ca2cf2

The earliest symptoms of AD are believed to be due to synaptic dysfunction, and in this context, numerous studies have established a significant role of the UPS in the regulation of synaptic plasticity.

Evidence 1852e34c7a

Synaptic loss has long been documented in AD brain (Gonatas et al. 1967) and, as expected, is strongly correlated with the degree of cognitive impairment (Terry et al. 1991).

Evidence d53a7df009

In transgenic mouse models of AD, synaptic deficits have been detected prior to the formation of amyloid plaques (Hsia et al. 1999).

Evidence 03854089ed

Similar therapeutic effects, including restoration of synaptic functions, are seen in APP mouse models after deleting cystatin C (Sun et al. 2008), by overexpressing cathepsin B (Mueller-Steiner et al. 2006), or by enhancing its activity (Butler et al. 2011).

Evidence a2a557c752

Neuronal endosome enlargement, which is not characteristically observed in other major neurodegenerative diseases, develops in pyramidal neurons of the neocortex at a stage when plaques and tangles are restricted only to the hippocampus (Braak stage 2) and not in brains of similarly aged individuals free of AD-like hippocampal pathology (Cataldo et al. 1997, 2000).

Evidence 2d7155aaaa

This finding suggests that neuropil threads may extend at both ends: Tau may aggregate and deposit first, followed by its ubiquitination.

Evidence d4a0927934

In vitro experiments further showed that aggregated (recombinant) tau—but not nonaggregated (monomeric) tau—can inhibit the proteasome activity.

Evidence 69bdb29520

This protein reactive with the initial anti-PHF sera was soon identified as tau, a microtubule-associated protein (MAP), based on its molecular weight, isoform change during development, microtubule- binding activity, and heat stability (Kosik et al. 1986; Nukina and Ihara 1986; see also Brion et al. 1985; Grundke-Iqbal et al. 1986; Wood et al. 1986; discovery of tau in PHF is reviewed in Mandelkow and Mandelkow 2011).

Evidence 21d5b6addc

Using well-characterized antibodies to various MAPs as well as PHF polyclonal antibodies, tau had recently been established as a major component of PHFs (see above and Mandelkow and Mandelkow 2011).

Evidence 1823ecc100

Besides the characteristic “PHF smear,” they also labeled a very small protein of ~8 kDa. Hiroshi Mori named these monoclonal antibodies DF (Dementia Filament) 1 and 2, of which the latter (DF2) was used for subsequent characterization (Mori et al. 1987).

Evidence 270708116a

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993).

Evidence 1ca57df2cc

However, recent work by Cripps et al. (2006) successfully used MC1 (a monoclonal specific for an abnormal PHF-like conformation of tau) to affinity purify soluble full-length tau from PHF-rich extracts of AD cortex and subject it to liquid chromatography–tandem MS (LC–MS/MS) analysis. The presence of K6, K11, and K48- linked polyubiquitinations—in addition to monoubiquitination—was observed.

Evidence d388360357

PHF have been associated with inhibition of the activity of the proteasome in a brain region–specific manner (Keller et al. 2000).

Evidence 5dca7e4687

Among the various molecular species of Abeta present in the brain, soluble oligomeric forms of Abeta are arguably the most plausible candidates to impair synaptic function (reviewed in Walsh and Selkoe 2004).

Evidence 9b8e41f357

Soluble Ab oligomers inhibit hippocampal long-term potentiation and alter memory and learning performance

Evidence 82d3e41083

They also facilitate long-term depression by, among other effects, disrupting synaptic glutamate uptake (Li et al. 2009).

Evidence 976448edaf

Recently, it has been shown that soluble Ab oligomers isolated from AD cortex can induce tau hyperphosphorylation at AD-relevant epitopes and subsequent neuritic degeneration (Jin et al. 2011).

Evidence eb27921c00

Moreover, soluble Ab oligomers themselves can inhibit proteasomal activity (Tseng et al. 2008).

Evidence 2a435556bd

Although less well studied as “Ab degrading proteases” than the zinc metallopeptidase family (Guenette 2003; Eckman et al. 2005), cathepsins are considered an important route for Ab/amyloid clearance (Mueller-Steiner et al. 2006; Nixon 2007; Butler et al. 2011) and human neurons may be particularly dependent on this mechanism (LeBlanc et al. 1999; reviewed in Saido and Leissring 2011).

Evidence 5cd26fae22

Cataclysmic disruption of lysosomal membranes releases hydrolases that act as both the trigger and executioner in rapid necrosis (Syntichaki et al. 2003; Kroemer et al. 2005), whereas slow release of cathepsins more likely operates through signaling pathways to trigger apoptosis (Kroemer et al. 2005).

Evidence 1c0525d948

Similar neuritic dystrophy eventually develops in all forms of AD and in mouse AD models where only FAD-causingmutant APP is overexpressed.

Evidence fcaccb4275

In addition, DF2 intensely labeled the classical granulovacuolar changes in the hippocampus in AD and other neurodegenerative disorders (Fig. 1, inset).

Evidence 5cfe823abe

Second, there is conjugation of the ATP-activated Ub to an E2 protein (i.e., a Ub-conjugating enzyme).

Evidence cf9b410365

Ubiquitin, the crucial signal for efficient sorting of proteins into the MVB (Babst et al. 1997), initiates this process, which is mediated by a group of ESCRT complexes (endosomal sorting complex required for transport; Hurley 2010).

Evidence d4b2a87946

In CMA, cytosolic proteins containing a KFERQ motif (including proteins pathogenic in some neurodegenerative diseases) are selectively targeted by certain chaperones to the lysosomal lumen for degradation (Arias et al. 2011).

Evidence 8f761efe46

Incomplete charperone-mediated autophagy of tau generates fragments that aggregate and are cleared by macroautophagy (Wang et al. 2009).

Evidence 32c84dd5e6

However, Ub was found to have other functional roles; for example, a proportion of histone (H)2B is ubiquitinated in a way that has a role in the transcription.

Evidence d62be44ad7

Pathological Rab5 activation driving endocytic dysfunction in AD may negatively impact longterm potentiation (LTP) and long-term depression (LTD) aspects of synaptic plasticity closely associated with learning and memory (Kessels et al. 2009)

Evidence 67f0c932c5

Microautophagy involves the nonselective entry of small quantities of cytoplasm into lysosomes or late endosomes/MVBs when the limiting membranes of these compartments invaginate and pinch off small vesicles for digestion within the lumen (Sahu et al. 2011).

Evidence c357d5d857

Similar autophagy pathology is observed when lysosomal proteolysis is inhibited (Ivy et al. 1984; Koike et al. 2005; Yang et al. 2008).

Evidence 63583fdc17

Indeed, when lysosomal proteolysis is inhibited by blocking acidification or directly inhibiting cathepsins,axonal transport of autophagy-related compartments is selectively slowed and intermittently interrupted.

Evidence 6ba3b0ee9d

A close connection between lysosomal network dysfunction and mechanisms of neurodegeneration is well documented (McCray et al. 2008; Nixon et al. 2008; Bellettato et al. 2010; Cherra et al. 2010).

Evidence 6542ec1fa0

In APP transgenic mouse models of AD, undigested autophagy substrates including LC3-II, p62, and ubiquitinated proteins accumulate in neuronal AVs, establishing that autophagic protein turnover in lysosomes is impeded (Yang et al. 2011).

Evidence eb5c912fa7

Stimulating lysosomal proteolytic efficiency in the TgCRND8 APP mouse model by deleting an endogenous inhibitor of lysosomal cysteine proteases (cystatin B) rescues lysosomal pathology, eliminates abnormal autolysosomal accumulation of autophagy substrates, including Ab, decreases Ab and amyloid deposition, and ameliorates learning and memory deficits (Yang et al. 2011)

Evidence 16af426ba4

Interactions between FAD-mutant forms of APP and APP binding protein (APP-BP1) on endosomes also initiate pathological rab5 activation, which was shown to promote a neuronal apoptosis cascade (Laifenfeld et al. 2007).

Evidence 1b5e647519

Interdependence of the proteasome and lysosomal system is also suggested by observations that, when proteasome activity is inhibited, proteins accumulate that become substrates for autophagy (Fortun et al. 2003)

Evidence 0bd4a57387

For example, p62, an adaptor protein for autophagy, also influences proteasomal degradation, whereas VCP/p97 acting through p62 and ubiquitin regulates both the proteasome-dependent endoplasmic reticulum–associated degradation (ERAD) pathway and aspects of autophagosome maturation (Tresse et al. 2010).

Evidence a8cc353415

The UPS is also critically involved in learning and memory.

Evidence d6cd663aad

This and numerous related findings suggest that degradation of certain critical proteins by the UPS is required during long-term memory formation. One of these proteins is arc, a negative regulator of synaptic strength that promotes the internalization of AMPA receptors and is degraded via the E3 ligase, UBE3A (Greer et al. 2010).

Evidence 3df3d413ed

Similar endosomal anomalies develop gradually in Down syndrome brain, beginning decades before the appearance of classical AD pathology (Cataldo et al. 2000).

Evidence 1fa17dc63e

Genes related to endocytosis, such as Rab5,Rab7, and Rab4, are among the earliest groups to showup-regulated transcription in AD(Ginsberg et al. 2010), and their corresponding proteins are abnormally recruited to endosomes, where they promote fusion and abnormal enlargement of early and late endosomes (Cataldo et al. 1997, 2008).

Evidence 7e4bd30d68

Although key to the survival of all cells, endocytosis supports unique neuronal functions, including aspects of synaptic transmission and plasticity underlying memory and learning.

Evidence 5a88068c6a

Autophagy may also modulate synaptic plasticity, which involves structural remodeling of nerve terminals (Boland et al. 2006) and the trafficking and degradation of receptors and other synaptic proteins (Leil et al. 2004; Rowland et al. 2006).

Evidence 5987033ee7

The acidic environment in lysosomes is particularly favorable for the initial stages of Ab oligomerization (Peralvarez-Marin et al. 2008).

Evidence e5179e81ce

AD is the most common of numerous age-associated brain diseases, and the activity of brain proteasomes appears to decline with age (Keller et al. 2002).

Evidence 55a5789feb

Beyond an age-related reduction (Keller et al. 2002), proteasome activities decrease in AD in a brain region–specific manner, particularly in hippocampus, parahippocampal gyrus, superior and middle temporal gyri, and the inferior parietal lobule (Keller et al. 2000), areas that are especially critical for long-term memory formation.

Evidence 249bffc88b

The lysosomal system, and specifically the autophagic pathway, is the principal mechanism for degrading proteins with long half-lives and is the only system in cells for degrading organelles and large protein aggregates or inclusions.

Evidence 5b3d101d04

Recently, protein aggregates and certain organelles have been shown to be tagged with ubiquination for selective removal by autophagy (Narendra et al. 2009; Dikic et al. 2010; Youle et al. 2011), a degradative process previously believed to be only nonselective

Evidence dac1e0c75d

Autophagy is the cell’s principal degradative pathway for eliminating unwanted organelles and long-lived proteins and for clearing damaged, aggregated, or obsolete proteins (Wong et al. 2010).

Evidence d0500a859b

Inhibiting autophagy by genetically deleting components of the sequestration machinery causes ubiquitinated protein aggregates to appear in neurons, reflecting additional negative effects on the UPS (Korolchuket al. 2009a,b).

Evidence 50936f6294

Indeed, many recent studies suggest the involvement of autophagy in the pathogenesis of AD

Evidence 7ff6173f27

A second route to lysosomes, the endocytic pathway, delivers extracellular material and plasma membrane constituents to lysosomes under the direction of specific targeting signals (Nixon 2004).

Evidence 78a39ed185

During macroautophagy, an elongated “isolation” membrane created from a preautophagosomal structure sequesters a region of cytoplasm to form a double- membrane-limited autophagosome (Fig. 5).

Evidence 35d48f28ab

The proteasome selectively degrades normal proteins (mainly those with short half-lives) and abnormal proteins, which are earmarked for elimination by a process involving their conjugation to ubiquitin (Ub; Goldberg 2003).

Evidence 9b55cb20ca

Proteins tagged with chains of four or more K48-linked multiubiquitins provide the strongest signal for degradation by the 26S proteasome, because a chain of at least four Ub moieties is required for substrate recognition by the 26S proteasome complex.

Evidence f4fb8c3ffc

Another study of AD brain tissues showed that hyperphosphorylated tau was bound to the proteasome, presumably to the 19S cap portion, and the more tau that was bound, the more that proteasomes appeared to be inhibited (Keck et al. 2003).

Evidence 0e402a09f7

During the induction of long-term facilitation in the snail, the regulatory subunit of cAMP-dependent protein kinase (PKA) is ubiquitinated and degraded by the proteasome, generating persistently activated PKA (Hegde et al. 1993).

Evidence 47110660ec

As regards the proteasome, both the ATP-dependent 26S proteasome and the ATP-independent 20S proteasome have been reported to degrade normal, soluble tau (Cardozo et al. 2002; Zhang et al. 2005).

Evidence 7a49a2c4a9

In 1997, a-synuclein was shown to be the principal component of Lewy bodies (Spillantini et al. 1997). The accumulated a-synuclein was then shown to be ubiquitinated (Hasegawa et al. 2002).

Evidence d493e85632

Amphisomes formed by the fusion of autophagosomes with early endosomes or MVBs/late endosomes are especially important in neurons, where a considerable proportion of endocytosed cargo is directed to the autophagic pathway prior to being degraded by lysosomes (Larsen et al. 2002).

Evidence 8f087181b1

Sequestered material within autophagosomes is digested when lysosomes or late endosomes fuse with the outer membrane of the autophagosome (Gordon et al. 1988).

Evidence c2ffbf72a1

Next, ubiquilin-1 has been reported to be genetically linked to AD

Evidence 9eb7392efd

Ubiquilin-1 interacts with both proteasomes and ubiquitinated proteins and regulates the proteasomal degradation of various proteins, including presenilin 1 (Haapasalo et al. 2010).

Evidence f7b2e62ab2

Based on these various findings, it has been speculated that small aggregates of PHFs may bind to the cap portion of the 26S proteasome and inhibit its activity

Evidence ead3b86216

Ubiquitinated target proteins bind to the 19S cap (RP), which has a Ub binding site and ATPase activity, and this leads to cleavage of Ub moieties from the target by deubiquitinating enzymes, unfolds the polypeptides and sends them to the narrow channel of the 20S core particle.

Evidence dffd6ee4e6

Third, there is ligation of Ub with an epsilon-amino group of lysine in the target protein by an E3 ligase. E3 ligase binds both the target protein and the E2–Ub complex; thousands of substrate- specific E3s ensure selective protein tagging and degradation.

Evidence 9f85c3b4c8

App promoter polymorphisms that increase APP expression are also associated with early-onset AD (Athan et al. 2002).

Evidence 836df09d7f

These findings support a longstanding hypothesis that the App gene on the trisomic copy of human chromosome 21 (HSA21) in Down syndrome (DS) is principally responsible for the invariant early development of AD in DS individuals (Margallo-Lana et al. 2004).

Evidence ac86cc5d14

In DS, the extra copy of App causes endocytic up-regulation and endosome pathology similar to that seen at the earliest stages of sporadic AD, but beginning even earlier

Evidence 3136615528

As described above, it has also been found that the 20S proteasome interacts with tau aggregates (Keck et al. 2003).

Evidence aca79dbf39

On the other hand, it has been reported that the E3 ligase CHIP (carboxyl terminus of the Hsc70-interacting protein) binds to tau and is involved in the degradation of abnormal forms of tau, including insoluble tau and hyperphosphorylated tau, coordinately with Hsp70 (Petrucelli et al. 2004; Dickey et al. 2006).

Evidence 82f7ff9185

The first step is activation of the carboxyl terminus of Ub by an E1 protein (i.e., a Ub-activating enzyme), which consumes ATP.

Evidence 4996485d21

Acceleration of endosome pathology is also seen in individuals who inherit the 14 allele of APOE, a key mediator of neuronal cholesterol transport and the major genetic risk factor for late-onset AD (Cataldo et al. 2000).

Evidence f2ff76a7d8

Expression of the ApoE epsilon 4 allele, but not ApoE epsilon 3, in mice administered a neprilysin inhibitor increases Ab immunoreactivity in lysosomes and causes neurodegeneration of hippocampal CA1, entorhinal,and septal neurons (Belinson et al. 2008).

Evidence 786c2860bf

ApoE epsilon4 that trafficks to lysosomes more readily than ApoE epsilon3, promotes leakage of acid hydrolases, and induces apoptosis in cultured neuronal cells by forming membrane-damaging intermediates in the low-pHenvironment (Ji et al. 2002).

Evidence a6de739cc8

Activated PKA induces transcription of ApUCH (UCH-L1 in mammals), a deubiquitinating enzyzme, which has been found to be critical for the induction of long-term facilitation (Hegde et al. 1997).

Evidence 30619e5eec

Recently, these effects of increased App dosage were shown to be mediated specifically by the b-cleaved carboxy-terminal fragment of APP, bCTF (Jiang et al. 2010), which binds to a complex of signaling molecules on endosomes that pathologically activates rab5 (S Kim and RA Nixon, unpubl.).

Evidence ea8e52857d

The currently prevailing view of the temporal involvement of Ub in PHF evolution is that the aggregation of hyperphosphorylated tau is followed by ubiquitination

Evidence dd839e9526

UBB+1 protein accumulates in brains affected by AD and other diseases such as Pick’s disease and Huntington’s disease (Fischer et al. 2003).

Evidence 222c4ade31

Indeed, transgenic mice expressing UBB+1 have an impaired UPS and show contextual memory deficits in both water maze and fear conditioning paradigms, without specific neuropathological findings (Fischer et al. 2009).

Evidence de94419ce8

The resulting polyubiquitinated UBB+1 cannot be degraded by proteasomes and impairs the UPS (Lam et al. 2000), which may induce neurotoxicity.

Evidence b9c49cd27a

In the absence of PS1, the V0a1 subunit of v-ATPase is not N-glycosylated in the ER and is degraded before sufficient amounts can be delivered to autolysosomes/lysosomes to support lysosomal acidification.

Evidence df37914516

Acid hydrolases, including cathepsins, are delivered from the trans-Golgi network (TGN) to MVBs/late endosomes by either of two mannose-6- phosphate receptors: cation-dependent 46 kDa MPR (CD-MPR) and cation-independent 215 kDa MPR (CI-MPR; Mullins et al. 2001).

Evidence cb04dae95b

In AD, tau is ubiquitinated, in Parkinson’s disease and dementia with Lewy bodies, it is a-synuclein, and in ALS and FTLD-U, it is TDP-43

Evidence 29de74c237

The E3 ligase Parkin, a protein implicated in Parkinson’s disease, creates an autophagy signal on mitochondria and also tags proteins elsewhere for proteasomal degradation (Yoshii et al. 2011).

Evidence 1786a34c2f

Beyond its role as a component of g-secretase, Presenilin 1 (PS1) is required for lysosome acidification, which is needed to activate cathepsins and other hydrolases that carry out digestion during autophagy (Lee et al. 2010).

Evidence b158cf2911

That presenilin 1 mutations, which are a cause of early-onset familial AD, impede lysosome proteolysis and accelerate neuritic dystrophy also supports a primary role for failure of proteolytic clearance (Lee et al. 2010).

Evidence ab80a1e90f

These observations suggest how PS1 mutations, which impede lysosomal acidification (Lee et al. 2010), may markedly accelerate and amplify neuritic dystrophy in AD

Evidence ae3f527367

Still other cargoes reach late endosomes when Rab7 and its effectors replace Rab5 and initiate further endosomal maturation (Poteryaev et al. 2010).

Evidence 859f38d798

Conversely, deletion of the neuronal rab5 GEF, rin1, reduces rab5 activation, increases LTP induction in the amygdala, and enhances fear learning and memory, most likely by increasing surface levels of AMPA receptors (Dhaka et al. 2003).

Evidence 39dd6f31f0

In this regard, the entity of frontotemporal lobar degeneration (FTLD) with Ub-positive/tau-negative inclusions was described later, and TDP43 was identified as the ubiquitinated protein in both this disorder and ALS (Neuman et al. 2006).

Evidence 5c33f76761

An E4 enzyme catalyzes the polyubiquitination of the target substrate that is bound to the E2–E3 complexes

Evidence f15955d8ba

An intronic polymorphism involving alternative splicing of exon 8 in the ubiquilin 1 gene (UBQLN1), which is genetically located near a well-established linkage peak for AD on chromosome 9q22, has been associated with increased risk for late-onset AD (Bertram et al. 2005).

Evidence f20eb2b34f

Although UCH-L1 is genetically associated with Parkinson’s disease (i.e., it is the PARK5 gene; Belin and Westerlund 2008), it has also been implicated in the pathogenesis of AD


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