Presynaptic Localization of Neprilysin Contributes to Efficient Clearance of Amyloid-β Peptide in Mouse Brain

Iwata, Nobuhisa; Mizukami, Hiroaki; Shirotani, Keiro; Takaki, Yoshie; Muramatsu, Shin‐ichi; Liu, Bao; Gerard, Norma P.; Gérard, Craig; Ozawa, Keiya; Saido, Takaomi C.

doi:10.1523/jneurosci.4792-03.2004

Cited by 224 publications

(192 citation statements)

References 47 publications

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“…Soluble materials from mouse cortical hemispheres were dissolved in Tris-HCl buffered saline (TS fraction) and the insoluble materials were dissolved in guanidine-HCl solution (GuHCl fraction) as previously described 46 . Samples from the brains and from the conditioned medium of MEFs were analyzed using an Aβ-ELISA kit (Wako) to quantify Aβ40.…”

Section: Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

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Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, found just as frequently in patient brains, remains unresolved. We generated knockin mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygous mice exhibited embryonic lethality, indicating that the mutation involves loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevation of Aβ43 levels, impairment of short-term memory, and acceleration of Aβ pathology, accompanying pronounced accumulation of Aβ43 in plaque cores similar to the biochemical composition observed in patient brains. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aȕ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic, and abundant in vivo. 3 Alzheimer's disease, the most common form of dementia, is characterized by two pathological features in the brain, extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques consist of amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. Two major forms of Aβ exist, Aβ40 and Aβ42, with Aβ42 being more neurotoxic due to its higher hydrophobicity, which results in faster oligomerization and aggregation 1 . A number of mutations associated with early-onset familial Alzheimer's disease (FAD) have been identified in the APP, PSEN1 and PSEN2 genes, and these mutations lead to accelerated production of Aβ42 or an increase in the Aβ42/Aβ40 ratio. Together these findings indicate that Aβ42 plays an essential role in the initiation of pathogenesis. However, the possible involvement of longer Aβ species that also exist in Alzheimer's disease brains has not yet been fully investigated.Thus far, various longer Aβ species, such as Aβ43, Aβ45, Aβ48, Aβ49 and Aβ50, have been qualitatively described in Alzheimer's disease brains 2 . Similar Aβ species have also been found in transgenic mice that overexpress APP carrying FAD-linked mutations 3 . Further quantitative studies have revealed that Aβ43 is deposited more frequently than Aβ40 in both sporadic Alzheimer's disease (SAD) and FAD [4][5][6][7] .How these Aβ species with different C-terminal ends are generated from the precursor has mainly been investigated by cell biological and biochemical methods. A number of studies 8,9 demonstrated that γ/ε-cleavage by γ-secretase activity controls the fate of the C-terminal end. Aβ43, generated from Aβ49 via Aβ46, is subsequently converted to Aβ40 by γ-secretase whereas Aβ42 is independently generated from Aβ48 via Aβ45. It has also been reported that the FAD-associated I213T mutation in the PSEN1 gene increases the generation of longer Aβ species, such as Aβ43, Aβ45 a...

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Section: Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

“…C42, C43 and MAB3402 (anti-GFAP antibody, Chemicon), with or without tyramide signal amplification (PerkinElmer Life Sciences) as previously described 46 .…”

Section: Immunohistochemical and Histochemical Studiesmentioning

confidence: 99%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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“…These findings might be clinically relevant given the fact that neprilysin expression in the brain decreases during aging and in the early stages of AD progression (Yasojima et al, 2001;Iwata et al, 2002), whereas elevated neprilysin activity reduces the accumulation of both soluble and fibrillar A in APP transgenic mice (Leissring et al, 2003;Iwata et al, 2004).…”

Section: Page 11 Of 31mentioning

confidence: 91%

Somatostatin and Alzheimer's disease

Burgos‐Ramos

Hervás-Aguilar

Aguado-Llera

et al. 2008

Molecular and Cellular Endocrinology

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“…In particular, NEP, ACE, and plasmin are considered to be physiologically and pathologically relevant in sporadic AD. NEP is a membrane-bound zinc metallopeptidase localized at the cell surface and in cytoplasmic vesicles preferentially hydrolyzing extracellular oligopeptides on the amino side of hydrophobic residues (53) and has been shown to be capable of degrading A␤ both in vivo (54,55) and in vitro (55)(56)(57). NEP is also reported to be expressed on neuronal pre-and postsynaptic membranes (52).…”

Section: Maldi-tof-ms Analysis Of Cleavage Products Of Npa␤ and Pa␤mentioning

confidence: 99%

Phosphorylation of Amyloid-β Peptide at Serine 8 Attenuates Its Clearance via Insulin-degrading and Angiotensin-converting Enzymes

Kumar

Singh

Hinze

et al. 2012

Journal of Biological Chemistry

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Background: Amyloid-␤ peptide (A␤) is degraded by different proteases. We recently demonstrated phosphorylation of A␤. Results: Phosphorylation of A␤ decreases its clearance by microglial BV-2 cells and selectively inhibits the cleavage by insulindegrading and angiotensin-converting enzymes. Conclusion: Phosphorylation at Ser-8 negatively regulates A␤ degradation. Significance: Phosphorylation could play a dual role in A␤ metabolism. It decreases the clearance by microglial cells and also promotes A␤ aggregation. Accumulation of amyloid-␤ peptides (A␤) in the brain is a common pathological feature of Alzheimer disease (AD).Aggregates of A␤ are neurotoxic and appear to be critically involved in the neurodegeneration during AD pathogenesis. Accumulation of A␤ could be caused by increased production, as indicated by several mutations in the amyloid precursor protein or the ␥-secretase components presenilin-1 and presenilin-2 that cause familial early-onset AD. However, recent data also indicate a decreased clearance rate of A␤ in AD brains. We recently demonstrated that A␤ undergoes phosphorylation by extracellular or cell surface-localized protein kinase A, leading to increased aggregation. Here, we provide evidence that phosphorylation of monomeric A␤ at Ser-8 also decreases its clearance by microglial cells. By using mass spectrometry, we demonstrate that phosphorylation at Ser-8 inhibited the proteolytic degradation of monomeric A␤ by the insulin-degrading enzyme, a major A␤-degrading enzyme released from microglial cells. Phosphorylation also decreased the degradation of A␤ by the angiotensin-converting enzyme. In contrast, A␤ degradation by plasmin was largely unaffected by phosphorylation. Thus, phosphorylation of A␤ could play a dual role in A␤ metabolism. It decreases its proteolytic clearance and also promotes its aggregation. The inhibition of extracellular A␤ phosphorylation, stimulation of protease expression and/or their proteolytic activity could be explored to promote A␤ degradation in AD therapy or prevention.Alzheimer disease (AD) 3 is characterized by the progressive deposition of amyloid-␤ peptides (A␤) in the brain (1, 2). A␤ derives from proteolytic processing of the amyloid precursor protein involving sequential cleavages by enzymes called ␤-and ␥-secretases (3, 4). A critical role of A␤ in the pathogenesis of AD is strongly supported by several mutations within the genes encoding the amyloid precursor protein itself or the two presenilins that represent the proteolytically active components of the ␥-secretase complex. All of these mutations affect the production and/or aggregation of A␤ and cause early-onset forms of familial AD (5-7). Although early-onset familial AD appears to be commonly associated with an elevated production of aggregation-prone A␤ variants, it remains unclear whether increased A␤ generation also contributes to the much more common form of late-onset AD. Recent evidence rather indicated a decreased clearance rate of A␤ in AD compared with control brains (8 -10).Several...

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Presynaptic Localization of Neprilysin Contributes to Efficient Clearance of Amyloid-β Peptide in Mouse Brain

Cited by 224 publications

References 47 publications

Potent amyloidogenicity and pathogenicity of Aβ43

Potent amyloidogenicity and pathogenicity of Aβ43

Somatostatin and Alzheimer's disease

Phosphorylation of Amyloid-β Peptide at Serine 8 Attenuates Its Clearance via Insulin-degrading and Angiotensin-converting Enzymes

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