PubMed: 21214928

APP processing in Alzheimer's disease.
Molecular brain
Xu H | Thompson R | Zhang YW | Zhang H

Evidence b9faa0f904

APP was found to colocalize with beta1 intergrins in neural cells [23]

Evidence 9ca943f0e7

Extracellular neuritic plaques are deposits of differently sized small peptides called beta-amyloid (Abeta) that are derived via sequential proteolytic cleavages of the b-amyloid precursor protein (APP) [6]

Evidence 7d451de367

In Down Syndrome (DS) patients, the accumulation of intracellular Abeta precedes extracellular plaque formation [148] and the level of intraneuronal Ab decreases as the extracellular Abeta plaques accumulate [149]

Evidence a697fbfd9e

While Abeta is neurotoxic, studies suggest that sAPPalpha is neuroprotective, making the subcellular distribution of APP an important factor in neurodegeneration [42-44]

Evidence cf8e6fd5c5

Multiple lines of evidence demonstrate that overproduction of Abeta results in a neurodegenerative cascade leading to synaptic dysfunction, formation of intraneuronal fibrillary tangles and eventually neuron loss in affected areas of the brain [6,142]

Evidence e6a4d3d4bf

Although excessive Abeta causes synaptic dysfunction and synapse loss [142], low levels of Abeta increase hippocampal longterm potentiation and enhances memory, indicating a novel positive, modulatory role on neurotransmission and memory [158,159]

Evidence e46d0cf6ee

Intraneuronal Abeta can also impair amygdala-dependent emotional responses by affecting the ERK/MAPK signaling pathway [153]

Evidence 17b8783a6d

Picomolar levels of Abeta can also rescue neuronal cell death induced by inhibition of Abeta generation (by exposure to inhibitors of beta- or gamma-scretases) [160], possibly through regulating the potassium ion channel expression, hence affecting neuronal excitability [161]

Evidence 2864a99bc6

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166]

Evidence 5f6e11a2ed

Indeed, phorbol ester’s effect on sAPPalpha secretion and Abeta generation though activation of protein kinase C (PKC) has been known for a long time [201-203]

Evidence 2899cf17be

We have found that estrogen may reduce Abeta levels by stimulating the alpha-secretase pathway and thereby inhibit Abeta generation

Evidence 8c4895d783

Interestingly, the stimulation of sAPPalpha secretion by estrogen can be blocked by a PKC inhibitor, suggesting the involvement of a PKC-dependent pathway [200]

Evidence 307d08e4bc

However, a recent study blocking the conversion of testosterone to estrogen found an estrogen-independent improvement in cognitive function and lowering of plaque formation along with a decrease in BACE1 mRNA, protein level, and activity [211]. In addition, testosterone may also reduce the protein level of PS1 [196]

Evidence 54cbc9aea6

However, overexpression of APP betaCTF was found to be cytotoxic and cause neuronal degeneration, perhaps by perturbing APP signal transduction [96,97]

Evidence c45210ce41

A recent report found that sAPPbeta can rescue gene expression of transthyretin and Klotho, which is decreased in APP/APLP2 deficient mice, but cannot rescue the lethality and neuromuscular synapse defects of these mice, suggesting a gene expression regulation function for sAPPbeta that is independent of developmental APP functions [95]

Evidence 65d1b622bf

A dramatically reduced ADAM10 protein level in the platelets of sporadic AD patients was also found to correlate with the significantly decreased sAPPalpha levels found in their platlets and cerebrospinal fluid [55] and the reduced alpha-secretase activity in the temporal cortex homogenates of AD patients [56]

Evidence 4afbe80cd9

In contrast to Abeta, sAPPalpha has an important role in neuronal plasticity/survival and is protective against excitotoxicity [42,43]. sAPPalpha also regulates neural stem cell proliferation and is important for early CNS development [57,58]

Evidence fade5e0e9d

We and others have also found that sAPPalpha can inhibit stress-induced CDK5 activation and participate in various neuroprotective reagent-mediated excitoprotection [44,59-61]

Evidence 38dbb76517

In a similar fashion, released AICD has been shown to possess transactivation activity and can regulate transcription of multiple genes including APP, GSK- 3b, KAI1, neprilysin, BACE1, p53, EGFR, and LRP1 [127-132]

Evidence 3801fbba74

In addition, free AICD can induce apoptosis and may play a role in sensitizing neurons to toxic stimuli [133,134]

Evidence 5f8bdafe8a

Abeta is generated from b-amyloid precursor protein (APP) through sequential cleavages first by beta-secretase and then by gamma-secretase complex

Evidence ee04e4104c

There are reports showing that the protein and mRNA levels of KPI-containing APP isoforms are elevated in AD brain and associated with increased Ab deposition [9]; and prolonged activation of extrasynaptic NMDA receptor in neurons can shift APP expression from APP695 to KPI-containing APP isoforms, accompanied with increased production of Ab [10]

Evidence 00deea5f70

Cleavage of APP by caspases may also contribute to AD pathologies

Evidence e99a852f87

It is also possible that APP betaCTF’s cytotoxic effect is actually mediated by the end products of gamma- and/or caspase-cleavage including APP intracellular domain (AICD), C31 and Jcasp which are cytotoxic (see below)

Evidence c60d7bc29f

In addition to secretases, caspases (predominantly caspase- 3) can directly cleave APP at position Asp664 (based on the APP695 sequence) within the cytoplasmic tail during apoptosis to release a fragment containing the last 31 amino acids of APP (called C31)

Evidence 1d73e8878a

Additional gamma-cleavage further generates the fragment (called Jcasp) containing the region between gamma- and caspase-cleavage sites

Evidence 7071280569

APP undergoes rapid anterograde transport in neurons

Evidence 24bcd948a2

A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19])

Evidence 63acc9dea1

Moreover, internalization of APP from the cell surface for endosomal/lysosomal degradation can be mediated by clathrin

Evidence 75cb7334a3

Although sAPPbeta only differs from sAPPalpha by lacking the Abeta1-16 region at its carboxyl-terminus, sAPPbeta was reported to function as a death receptor 6 ligand and mediate axonal pruning and neuronal cell death [94]

Evidence cc1099f5d0

Rab6, a member of the GTP-binding protein family of membrane trafficking regulators, is implicated in protein transport along biosynthetic and endocytic pathways and has also been found to affect APP processing

Evidence 5d9af3635c

The APP gene is located on chromosome 21 in humans with three major isoforms arising from alternative splicing [3]. These are APP695, APP751 and APP770 (containing 695, 751, and 770 amino acids, respectively)

Evidence f7df83b618

APP alphaCTF and betaCTF are further cleaved by gamma-secretase to generate p83 and Abeta, respectively

Evidence 36d343635a

In addition to cleaving APP CTFs, gamma-secretase cleaves a series of functionally important transmembrane proteins, including Notch [120], cadherin [114], tyrosinase [121], ErbB4 [79], CD44 [70], etc.) (see review [122])

Evidence 377d52f059

Overall, most studies suggest that APP plays some role in regulating protein trafficking

Evidence 5c8204ab70

Inhibition of dynamin-mediated but not clathrin-mediated Abeta internalization was also found to reduce Abeta-induced neurotoxicity [154]

Evidence 556738cc69

Recently, a novel gamma-secretase activating protein (GSAP) was identified and GSAP was found to selectively increase Abeta production through interaction with both gamma-secretase and the APP CTF substrate [117]

Evidence c4fb12dcd5

One possible mechanism for C31’s toxicity is that C31 complexes with APP to recruit the interacting partners that initiate the signals related to cellular toxicity [136]

Evidence aa2e65b24a

For example, the APP C-terminus has been found to interact with all three mint (X11) family members (mint1, mint2, and mint3) involved in trafficking regulation [163-165]

Evidence ddca579589

During its transport, APP was found to interact with kinesin-I and functions as a kinesin-I membrane receptor to mediate axonal transport of beta-secretase (BACE1) and PS1 [26,27]

Evidence d55810b475

Antagonizing the extracellular interaction between cell-surface APP and LRP increased the level of cell surface APP while decreasing Abeta generation [187]

Evidence dd03a2c46c

An LRP-related protein 1B (LRP1B) has a similar effect, binding APP at the plasma membrane, preventing APP internalization, and leading to decreased Abeta generation and increased sAPPalpha secretion [189]

Evidence 15f42512a2

One study showed that the ectodomain of Nicastrin binds to APP and Notch and can recruit them into the g-secretase complex, suggesting that Nicastrin may act as the gamma-secretase receptor [108]

Evidence d38c6613bf

On the other hand, Golgi-localized gamma-ear-containing ARF-binding (GGA) proteins have been found to interact with BACE1 and regulate its trafficking between the late Golgi and early endosomes; and depletion of GGA proteins increases the accumulation of BACE1 in acidic early endosomes for enhanced BACE1 stability and cleavage of APP [76-78]

Evidence cf92e93a53

The first step in Abeta generation is cleavage of APP by the beta-secretase

Evidence 9103914a48

These results provide convincing evidence that BACE1 is the beta-secretase involved in APP metabolism [63-67]; and BACE1 activity is thought to be the rate-limiting factor in Abeta generation from APP

Evidence 1d332bdab4

BACE1 deficiency in AD model mice have been shown to rescue cholinergic dysfunction, neuronal loss and memory deficits, correlating with a dramatic reduction in Abeta40/42 levels [79-81]

Evidence 4074233aa9

Some studies found that BACE1 can interact with reticulon/Nogo proteins, whose increased expression can block BACE1 in the ER with a neutral pH environment and thus inhibit BACE1 activity in Abeta generation [73-75]

Evidence 50acf2a31a

This PS1-PLD1 interaction recruits PLD1 to the Golgi/TGN and thus potentially alters APP trafficking as PLD1 overexpression promotes budding of vesicles from the TGN containing APP and increases cell surface levels of APP [176,177]

Evidence 65ac4868ea

We and others have shown that PS1 can also regulate the intracellular trafficking of APP

Evidence 32134cd517

Co-expression of ADAM9 with APP promoted sAPPalpha production upon phorbol ester treatment, suggesting that ADAM9 possesses alpha-secretase activity [51]

Evidence a3ccda7cc1

APP751 and APP770 are expressed in most tissues and contain a 56 amino acid Kunitz Protease Inhibitor (KPI) domain within their extracellular regions

Evidence 7077656569

Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain to release soluble APPa and preclude Abeta generation

Evidence 17a125ffb1

Cleavage of APP by alpha-secretase precludes Abeta generation as the cleavage site is within the Abeta domain (at the Lys16- Leu17 bond), and releases a large soluble ectodomain of APP called sAPPalpha

Evidence 981030bc07

From the TGN, APP can be transported in TGN-derived secretory vesicles to the cell surface where it is either cleaved by alpha-secretase to produce a soluble molecule, sAPPalpha [37], or re-internalized via an endosomal/ lysosomal degradation pathway [38,39]

Evidence edf27cc95c

Manipulation of ADAM17 can alter alpha-cleavage of APP and Abeta generation, with regulated alpha-cleavage abolished in ADAM17-deficient cells, suggesting that ADAM17 is likely the alpha-secretase responsible for regulated APP cleavage [47]

Evidence 47c870a799

There are two main toxic species, Ab40 and Ab42, with Abeta42 more hydrophobic and more prone to fibril formation while only making up about 10% of the Abeta peptide produced [143]

Evidence 0bfe42edc0

Studies done on familial AD (FAD) mutations consistently show increases in the ratio of Abeta42/40 [105,144], suggesting that elevated levels of Abeta42 relative to Abeta40 is critical for AD pathogenesis, probably by providing the core for Abeta assembly into oligomers, fibrils and amyloidogenic plaques [145,146]

Evidence 3b81a870d2

As DS also results in Abeta accumulation, the genes location suggests a link between BACE2 and APP processing

Evidence 56484ecf64

Indeed, BACE2 cleaves beta-secretase substrates such as wild-type and Swedish mutant APP, similar to BACE1, in enzymatic In vitro assays [89]

Evidence 9623c1033b

Downregulation of CD147 increases Abeta production but its overexpression has no effect on Abeta generation [113]

Evidence fa3ece4899

Inhibition of cathepsin B has been found to reduce Abeta production both in vivo and in vitro [92,93]

Evidence 875693dc4b

The neurofibrillary tangles (NFTs) consist largely of hyperphosphorylated twisted filaments of the microtubule-associated protein tau [4,5]

Evidence a27e639416

In support of this, protein kinase A (PKA) has similar effects on reducing Abeta generation and stimulating the budding of APP-containing vesicles from the TGN [207]

Evidence a784f94665

PKC stimulates sAPPalpha secretion, reducing Abeta levels, even when the phosphorylation sites on APP are mutated or the entire cytoplasmic domain is deleted [204]

Evidence 031daac6f3

While PKC can directly phosphorylate APP Ser655 [205], it appears to affect APP metabolism by phosphorylating a different target

Evidence 4861fdad7c

Additionally, estrogen has been found to facilitate binding of Rab11 to the TGN membrane and a dominant negative Rab11 mutant abolishes the estrogen-regulated change in APP trafficking, leading to increased Abeta formation [197]

Evidence 36170edfec

Recently it was found that SorLA/ LR11 overexpression redistributed APP to the Golgi, decreasing Abeta generation, while SorLA/LR11 knockout mice have increased levels of Abeta, as found in AD patients [182]

Evidence 3b8804d7f0

However, another study failed to confirm the binding of TMP23/p21 to gamma-secretase, but rather suggested that TMP21/p23, which belongs to the p24 cargo family involved in vesicular trafficking regulation, influences APP trafficking and thus Abeta generation [116]


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