Neuronal neprilysin overexpression is associated with attenuation of Aβ-related spatial memory deficit

Poirier, Roseline; Wolfer, David P; Welzl, Hans; Tracy, Jay; Galsworthy, Michael J.; Nitsch, Roger M.; Mohajeri, M. Hasan

doi:10.1016/j.nbd.2006.08.003

Cited by 55 publications

(60 citation statements)

References 63 publications

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“…When the APP/⌬PS1-Tg mice were treated with NEP lentiviruses there was a significant decrease in the circling behavior suggesting an improvement in the spatial orientation. Our results are consistent with recently published studies 33,74 reporting that NEP/APP double-transgenic mice showed a reduction in amyloid load in the brain of aged mice, reduction in glial cells, and an improved Morris water maze memory performance. Thus, these data collectively confirm the importance of A␤ peptide-lowering strategies at early stages of the disease to prevent the A␤ peptide-related cognitive decline.…”

Section: Discussionsupporting

confidence: 93%

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

El‐Amouri

Zhu

et al. 2008

The American Journal of Pathology

164

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: 93%

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

El‐Amouri

Zhu

et al. 2008

The American Journal of Pathology

164

132

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“…Transgenic (13,14), viral (15,16), or ex vivo delivery (17) of NEP to brains of APP transgenic mice reduces extracellular amyloid deposits, synaptic dysfunction, and premature death. Intraneuronal accumulations of A␤42 have also been detected in AD brains (18,19) and may contribute to AD pathogenesis.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Overexpression of Neprilysin Reduces Alzheimer Amyloid-β42 (Aβ42)-induced Neuron Loss and Intraneuronal Aβ42 Deposits but Causes a Reduction in cAMP-responsive Element-binding Protein-mediated Transcription, Age-dependent Axon Pathology, and Premature Death in Drosophila

Iijima-Ando

Hearn

Granger

et al. 2008

Journal of Biological Chemistry

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The amyloid-␤42 (A␤42) peptide has been suggested to play a causative role in Alzheimer disease (AD). Neprilysin (NEP) is one of the rate-limiting A␤-degrading enzymes, and its enhancement ameliorates extracellular amyloid pathology, synaptic dysfunction, and memory defects in mouse models of A␤ amyloidosis. In addition to the extracellular A␤, intraneuronal A␤42 may contribute to AD pathogenesis. However, the protective effects of neuronal NEP expression on intraneuronal A␤42 accumulation and neurodegeneration remain elusive. In contrast, sustained NEP activation may be detrimental because NEP can degrade many physiological peptides, but its consequences in the brain are not fully understood. Using transgenic Drosophila expressing human NEP and A␤42, we demonstrated that NEP efficiently suppressed the formation of intraneuronal A␤42 deposits and A␤42-induced neuron loss. However, neuronal NEP overexpression reduced cAMP-responsive element-binding protein-mediated transcription, caused age-dependent axon degeneration, and shortened the life span of the flies. Interestingly, the mRNA levels of endogenous fly NEP genes and phosphoramidon-sensitive NEP activity declined during aging in fly brains, as observed in mammals. Taken together, these data suggest both the protective and detrimental effects of chronically high NEP activity in the brain. Down-regulation of NEP activity in aging brains may be an evolutionarily conserved phenomenon, which could predispose humans to developing late-onset AD. Alzheimer disease (AD)3 is a progressive neurodegenerative disease defined by two protein deposits in autopsied brains: extracellular amyloid plaques composed of the 40-or 42-amino acid ␤-amyloid peptides (A␤40 or A␤42), and intracellular neurofibrillary tangles composed of abnormally hyperphosphorylated microtubule-associated protein Tau (1). A␤ peptides are physiological metabolites of the amyloid precursor protein (APP) resulting from sequential cleavage by ␤-secretase and ␥-secretase complex, whose catalytic subunits are presenilin 1 (PS1) and presenilin 2 (PS2) (2). Molecular genetic studies of early onset familial AD patients have identified causative mutations in APP, PS1, and PS2 genes, and these mutations promote A␤42 production, aggregation, and stability against clearance (3). Thus, the increased A␤42 levels in the brain are believed to initiate AD pathogenesis.The mechanisms by which A␤42 reaches pathological levels in the brains of late-onset AD (LOAD) patients are not well understood. The steady state level of A␤42 in the brain reflects the balance between production and clearance, and a reduction in clearance activity would raise A␤42 levels. A deficiency in neprilysin (NEP), a major rate-limiting A␤-degrading enzyme (4, 5), accelerates formation of extracellular amyloid deposits (6), amyloid angiopathy (6), synaptic dysfunctions (7), and memory defects (7) caused by human A␤ in transgenic mice. In LOAD patients, NEP mRNA and pro-

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“…For example, decreased expression of insulin degrading enzyme (IDE) or neprilysin -both of which are known to degrade Aβ-leads to increased accumulation of Aβ, and ultimately to AD. In contrast, overexpression of these enzymes reduces Aβ levels and attenuates Aβ-related memory deficit [16][17][18][19][20] . Together, these studies provide a compelling case for the role of Aβ aggregation in the pathogenesis of Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

Mutations Enhance the Aggregation Propensity of the Alzheimer’s Aβ Peptide

Kim

Hecht

2008

Journal of Molecular Biology

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Aggregation of the amyloid β peptide (Aβ) plays a key role in the molecular etiology of Alzheimer's disease. Despite the importance of this process, the relationship between the sequence of Aβ and the propensity of the peptide to aggregate has not been fully elucidated. The sequence determinants of aggregation can be revealed by probing the ability of amino acid substitutions (mutations) to increase or decrease aggregation. Numerous mutations that decrease aggregation have been isolated by laboratory-based studies. In contrast, very few mutations that increase aggregation have been reported, and most of these were isolated from rare individuals with early onset Familial Alzheimer's disease. To augment the limited data set of clinically derived mutations, we developed an artificial genetic screen to isolate novel mutations that increase aggregation propensity. The screen relies on expression in E. coli of a fusion of Aβ to green fluorescent protein (GFP). In this fusion, the ability of the GFP reporter to fold and fluoresce is inversely correlated with the aggregation propensity of the Aβ sequence. Implementation of this screen enabled the isolation of 20 mutant versions of Aβ with amino acid substitutions at 17 positions in the 42-residue sequence of Aβ. Biophysical studies of synthetic peptides corresponding to sequences isolated by the screen confirm the increased aggregation propensity and amyloidogenic behavior of the mutants. The mutations were isolated using an unbiased screen that makes no assumptions about the sequence determinants of aggregation. Nonetheless, all 16 of the most aggregating mutants contain substitutions that reduce charge and/or increase hydrophobicity. These findings provide compelling evidence supporting the hypothesis that sequence hydrophobicity is a major determinant of Aβ aggregation.

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Neuronal neprilysin overexpression is associated with attenuation of Aβ-related spatial memory deficit

Cited by 55 publications

References 63 publications

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

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

Overexpression of Neprilysin Reduces Alzheimer Amyloid-β42 (Aβ42)-induced Neuron Loss and Intraneuronal Aβ42 Deposits but Causes a Reduction in cAMP-responsive Element-binding Protein-mediated Transcription, Age-dependent Axon Pathology, and Premature Death in Drosophila

Mutations Enhance the Aggregation Propensity of the Alzheimer’s Aβ Peptide

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