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

Abstract

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...

Exceptional Amyloid β Peptide Hydrolyzing Activity of Nonphysiological Immunoglobulin Variable Domain Scaffolds

“…For example, from its k cat value in Table 1, a single IgV L -tЈ 5D3 molecule is predicted to digest 4320 A␤ molecules in 3 days at excess A␤ concentration. The enzyme neprilysin has received attention as a potential A␤-clearing AD drug (52). The k cat of neprilysin for A␤ is comparable with the IgVs reported here (53).…”

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

“…The primary effect of IDE is degradation of Aβ polymers and fibers Qiu and Folstein 2006), while NEP is used predominantly in degradation of Aβ monomers and oligomers (El-Amouri et al 2008). Our results show that IDE content in the hippocampus of APP/PS1 mice clearly decreases, whereas NEP levels do not differ from those in WT controls.…”

Neprilysin-2 Is an Important β-Amyloid Degrading Enzyme

“…The results of these therapeutic studies showed reduced plaque pathology and memory improvements in treated animals. 21,[27][28][29][30][31][32][33][34][35] However, because current approaches could ultimately be ineffective or produce unwanted side effects, 36 -38 more tools are always welcome in the search for therapies for AD, and exploration of the potential of NEP2 as a therapeutic agent is warranted.…”