Loss of Neprilysin Function Promotes Amyloid Plaque Formation and Causes Cerebral Amyloid Angiopathy

Farris, Wesley; Schütz, Sonja G.; Cirrito, John R.; Shankar, Ganesh M.; Sun, Xiaoyan; George, Ana; Leissring, Malcolm A.; Walsh, Dominic M.; Qiu, Wei Qiao; Holtzman, David M.; Selkoe, Dennis J.

doi:10.2353/ajpath.2007.070105

Cited by 140 publications

(111 citation statements)

References 54 publications

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“…Because this mouse model of AD has been reported to develop cerebral amyloid angiopathy at ϳ7 months of age, 66 loss of NEP function would promote cerebral amyloid angiopathy. 35 Likewise, these results are in agreement with clinical studies, which suggest that nonsteroidal anti-inflammatory drugs, such as those used in arthritis, may delay or slow the progression of AD. 45,46 However, a major impediment to using of this class of drugs for treatment of AD is the number of serious side effects associated with the chronic use of nonsteroidal anti-inflammatory drugs such as gastric bleeding, heart attack, and stroke.…”

Section: Discussionsupporting

confidence: 82%

“…The effect at a distance of NEP overexpression on the clearance of A␤ peptide in the brain and body fluids was also reported elsewhere. 35,36 Disruption of NEP in mice resulted in increased A␤ peptide in the whole brain and plasma.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, NEP has a high affinity toward A␤ peptide compared to other small neuropeptides 10,31,35 and, in the AD brain, up-regulation of NEP activity will be mostly directed to degrade excess A␤ peptide. Thus, gene therapy of NEP represents a potential therapeutic approach for AD.…”

Section: Discussionmentioning

confidence: 99%

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Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease

El‐Amouri

Zhu

et al. 2008

The American Journal of Pathology

165

132

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It is well established that the extracellular deposition of amyloid ␤ (A␤) peptide plays a central role in the development of Alzheimer's disease (AD). Therefore, either preventing the accumulation of A␤ peptide in the brain or accelerating its clearance may slow the rate of AD onset. Neprilysin (NEP) is the dominant A␤ peptide-degrading enzyme in the brain; NEP becomes inactivated and down-regulated during both the early stages of AD and aging. In this study, we investigated the effect of human (h)NEP gene transfer to the brain in a mouse model of AD before the development of amyloid plaques, and assessed how this treatment modality affected the accumulation of A␤ peptide and associated pathogenetic changes (eg, inflammation, oxidative stress, and memory impairment). Overexpression of hNEP for 4 months in young APP/⌬PS1 double-transgenic mice resulted in reduction in A␤ peptide levels, attenuation of amyloid load, oxidative stress, and inflammation, and improved spatial orientation. Moreover, the overall reduction in amyloidosis and associated pathogenetic changes in the brain resulted in decreased memory impairment by ϳ50%. These data suggest that restoring NEP levels in the brain at the early stages of AD is an effective strategy to prevent or attenuate disease progression. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a loss of neurons in discrete regions of the brain, particularly in the cortex and hippocampus.1,2 The neuronal loss is accompanied by extracellular deposition of A␤ peptide in a form of senile plaques and intracellular accumulation of neurofibrillary tangles made of a hyperphosphorylated form of the microtubule-associated protein tau.3 Clinically, AD is characterized by a gradual decline in cognition, and changes in behavior and personality including difficulty in reasoning, disorientation, and language problems. The exact cause of AD is not yet clear, but it is widely assumed that accumulation and aggregation of A␤ peptide is the initial trigger for a complex, multistep cascade that includes gliosis, inflammatory changes, oxidative stress, neuritic/ synaptic changes, tangle formation (microtubule changes), and neurotransmitter loss, leading to dementia. 4 Therefore, lowering the A␤ peptide levels in the brain would stop or delay the onset of AD. NEP as one of the A␤ peptide-degrading enzymes, has been reported to play a key role in regulating the level of A␤ peptide in the brain. 5,6 NEP [neprilysin, previously called CD10 or common acute lymphoblastic leukemia antigen (CALLA)] is a type II membrane metalloendopeptidase composed of ϳ750 residues (ϳ110 kDa) with an active site containing a zinc-binding motif (HEXXH) at the extracellular carboxyl terminal domain.7-10 NEP is capable of degrading the monomeric and (possibly) the oligomeric forms of A␤ peptide. 11,12 In recent years several reports have indicated that the soluble (eg, oligomeric) forms of A␤ peptide play a significant role in memory impairment and AD, [13][14][15] however, it is noteworthy t...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease

El‐Amouri

Zhu

et al. 2008

The American Journal of Pathology

165

132

View full text Add to dashboard Cite

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“…Experimental depletion of endogenous NEP activity by pharmacological inhibitors (Iwata et al 2000;Hauss-Wegrzyniak and Wenk 2002;Newell et al 2003;Mouri et al 2006) or reduction of NEP expression by molecular approaches (Madani et al 2006;Farris et al 2007) results in neural accumulation of Ab. Conversely, experimental manipulations that increase brain expression of NEP also increase Ab catabolism and reduce Ab burden (Leissring et al 2003;Marr et al 2003;Hong (Ramsden et al 2003;Rosario et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

Yao

Nguyen

Rosario

et al. 2008

Journal of Neurochemistry

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Age‐related testosterone depletion in men is a risk factor for Alzheimer’s disease. Prior studies suggest that androgens affect Alzheimer’s disease risk by regulating accumulation of β‐amyloid protein (Aβ) by an undefined mechanism. In this study, we investigated the role of the Aβ‐catabolizing enzyme neprilysin (NEP) in this process. First, we observed that androgens positively regulate neural expression of NEP in adult male rats. Next, we investigated androgen regulatory effects on both NEP expression and Aβ levels using cultured hippocampal neurons and neuronally differentiated rat pheochromocytoma cell 12 with or without androgen receptor (AR). Dihydrotestosterone (DHT) induced a time‐dependent increase in NEP expression. DHT also significantly decreased levels of Aβ in AR‐expressing cells transfected with amyloid precursor protein, but did not affect levels of either full‐length or non‐amyloidogenic, soluble amyloid precursor protein. Importantly, the DHT induced decrease of Aβ was blocked by pharmacological inhibition of NEP. The DHT‐mediated increase in NEP expression and decrease in Aβ levels were (i) not observed in rat pheochromocytoma cell 12 lacking AR and (ii) blocked in AR‐expressing cells by the antagonists, cyproterone acetate and flutamide. Together, these findings suggest that androgen regulation of Aβ involves an AR‐dependent mechanism requiring up‐regulation of the Aβ catabolizing enzyme NEP.

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“…Этиология ее возникновения и развития имеет много-факторную природу. Одним из факторов, способству-ющих возникновению спорадической формы БА, явля-ется нарушение катаболизма Аβ и его выведение из нервной ткани [14], часто обусловленное снижением активности амилоид-деградирующих ферментов, в частности неприлизина (EC3.4.24.11, нейтральная эн-допептидаза, НЕП) [7,15,16], а также нарушением ха-рактера связывания Аβ с белками-переносчиками, как, например, в случае экспрессии аллели АроЕ ε4 [17].…”

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