Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of β-amyloid peptide

Yasojima, Koji; Akiyama, Haruhiko; McGeer, Edith G.; McGeer, Patrick L.

doi:10.1016/s0304-3940(00)01675-x

Cited by 337 publications

(237 citation statements)

References 9 publications

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“…Similar findings have been reported in humans; decreased neprilysin mRNA levels were found to be associated with areas of high amyloid plaque burdens, colocalizing with increased APP and PS mRNA levels (Yasojima et al, 2001a). This inverse correlation is further supported by immunohistochemical localization of neprilysin in similar areas of the human brain (Akiyama et al, 2001;Yasojima et al, 2001b). Although it has been demonstrated that the infusion of Nep inhibitors can accelerate A␤ deposition and that Nep induction is correlated with reduced A␤ deposition (Iwata et al, 2000;Mohajeri et al, 2002), to our knowledge no direct effect on the accumulation of A␤ deposits had been established for Nep in vivo.…”

Section: Discussionsupporting

confidence: 79%

Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

et al. 2003

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The degenerative process of Alzheimer's disease is linked to a shift in the balance between amyloid-␤ (A␤) production, clearance, and degradation. Neprilysin has recently been implicated as a major extracellular A␤ degrading enzyme in the brain. However, there has been no direct demonstration that neprilysin antagonizes the deposition of amyloid-␤ in vivo. To address this issue, a lentiviral vector expressing human neprilysin (Lenti-Nep) was tested in transgenic mouse models of amyloidosis. We show that unilateral intracerebral injection of Lenti-Nep reduced amyloid-␤ deposits by half relative to the untreated side. Furthermore, Lenti-Nep ameliorated neurodegenerative alterations in the frontal cortex and hippocampus of these transgenic mice. These data further support a role for neprilysin in regulating cerebral amyloid deposition and suggest that gene transfer approaches might have potential for the development of alternative therapies for Alzheimer's disease.

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Section: Discussionsupporting

confidence: 79%

Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

et al. 2003

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“…This result is also consistent with the feature of hippocampal Aβ load, wherein the percentage of area occupied by thioflavin-S-positive fibrillary plaques is higher than 6E10-immunopositive diffuse plaques. Unlike aged APP/PS mice, previous studies have reported that the protein levels and activities of NEP are significantly decreased in the brain of patients with AD, while IDE is not significantly altered (Yasojima et al 2001;Caccamo et al 2012;Wang et al 2005). Therefore, for AD patients, impaired Aß clearance could be mainly due to decreased degradation of Aβ monomers and oligomers, whereas, for aged APP/PS1 mice, it is primarily attributed to reduced degradation of Aβ polymers and fibers.…”

Section: Discussionmentioning

confidence: 85%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

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“…In the brain, NEP is expressed on the membranes of neurons. NEP mRNA and protein are significantly decreased in AD brains compared with agematched normal brains (18,19). An age-related decline of NEP has also been reported in mouse hippocampus (20).…”

mentioning

confidence: 97%

Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model

Yue

Lu²,

Lancaster³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

337

306

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Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age-and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examined the onset and severity of AD pathology associated with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased ␤ amyloid peptide (A␤) deposition. These mice also exhibited increased A␤ production, and microglia cultures prepared from the brains of these mice were impaired in A␤ clearance͞degradation. In contrast, ovariectomized APP23 mice exhibited plaque pathology similar to that observed in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.amyloid deposition ͉ aromatase ͉ transgenic animal N europathological hallmarks of Alzheimer's disease (AD) include significant deposition of extracellular ␤ amyloid peptide (A␤) and presence of neurofibrillary tangles in the brain (1). A␤ is derived from the two-step enzymatic processing of amyloid precursor protein (APP) in which ␤-secretase (BACE) cleaves the ␤-site of APP to release the N terminus of A␤, and the ␥-secretase protein complex cleaves the ␥-site of APP to release the C terminus of A␤ (2, 3). Overproduction and progressive deposition of A␤ are known to underlie, in part, A␤ plaque formation, a key pathologic feature of AD. The initial cleavage of APP by BACE is critical for A␤ associated with AD neuropathology (4). Recent studies have shown that BACE activity increases with age and is elevated in AD brains (5, 6).Impaired A␤ clearance and͞or degradation may also contribute to A␤ plaque formation. Our previous findings support this hypothesis: Microglia isolated from AD brains have impaired phagocytic activity, leading to reduced A␤ clearance (7). Other groups have found that cytoplasmic A␤ granules in the plaque-associated glia and microglia participate in the clearance of A␤ in A␤-immunized AD patients and APP transgenic mice (8, 9).Two enzymes are involved in A␤ degradation and clearance: insulin-degrading enzyme (IDE) and neprilysin (NEP). IDE is expressed in high concentrations in the brain. Besides degrading insulin and several regulatory peptides, IDE also degrades the intracellular domain of APP and is responsible for degrading and clearing A␤ from the brain (10, 11). Indeed, genetic linkage studies have shown that late-onset AD loci on chromosome 1...

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Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of β-amyloid peptide

Cited by 337 publications

References 9 publications

Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model

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