Blood–brain barrier penetrating neprilysin degrades monomeric amyloid-beta in a mouse model of Alzheimer’s disease

Rofo, Fadi; Metzendorf, Nicole G.; Saubi, Cristina; Suominen, Laura; Godec, Ana; Sehlin, Dag; Syvänen, Stina; Hultqvist, Greta

doi:10.1186/s13195-022-01132-2

Cited by 17 publications

(3 citation statements)

References 70 publications

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“…[93][94][95] Neprilysin injections decreased amyloid-beta oligomers in an AD mouse model. 93 Cacna1c, a psychiatric risk gene identified as an AD-risk gene by GWAS, 96 encodes a calcium channel. Expression of the CACNA1C protein was previously identified as increased in the hippocampus of the transgenic AD mouse model APP/PS1.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

Soelter,

Howton,

Wilk

et al. 2024

Preprint

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Alzheimer's disease (AD) is the most common form of dementia and is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology of AD includes the formation of extracellular amyloid-β ; plaque and intracellular neurofibrillary tangles of phosphorylated tau, along with neuronal loss. While neuronal loss is an AD hallmark, cell-cell communication between neuronal and non-neuronal cell populations maintains neuronal health and brain homeostasis. To study changes in cell-cell communication during disease progression, we performed snRNA-sequencing of the hippocampus from female 3xTg-AD and wild-type littermates at 6 and 12 months. We inferred differential cell-cell communication between 3xTg-AD and wild-type mice across time points and between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) of interest. We also assessed the downstream effects of altered glia-neuron communication using pseudobulk differential gene expression, functional enrichment, and gene regulatory analyses. We found that glia-neuron communication is increasingly dysregulated in 12-month 3xTg-AD mice. We also identified 23 AD-associated ligand-receptor pairs that are upregulated in the 12-month-old 3xTg-AD hippocampus. Our results suggest increased AD association of interactions originating from microglia. Signaling mediators were not significantly differentially expressed but showed altered gene regulation and TF activity. Our findings indicate that altered glia-neuron communication is increasingly dysregulated and affects the gene regulatory mechanisms in neurons of 12-month-old 3xTg-AD mice.

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Section: Discussionmentioning

confidence: 99%

“…MME encodes neprilysin, an enzyme responsible for amyloid-β degradation. [93][94][95] Neprilysin injections decreased amyloid-beta oligomers in an AD mouse model. 93 Cacna1c, a psychiatric risk gene identified as an AD-risk gene by GWAS, 96 encodes a calcium channel.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

Soelter,

Howton,

Wilk

et al. 2024

Preprint

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“…Further mass spectrometry analysis has provided greater resolution to the exact nature of Ab cleavage [139]. Presently, it is clear that NEP can degrade monomeric Ab; however, there is also some evidence for oligomer degradation [140][141][142].…”

Section: Neprilysin (Nep)mentioning

confidence: 99%

Molecular basis of selective amyloid‐β degrading enzymes in Alzheimer's disease

Żukowska,

Moss,

Subramanian

et al. 2023

The FEBS Journal

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The accumulation of the small 42‐residue long peptide amyloid‐β (Aβ) has been proposed as a major trigger for the development of Alzheimer's disease (AD). Within the brain, the concentration of Aβ peptide is tightly controlled through production and clearance mechanisms. Substantial experimental evidence now shows that reduced levels of Aβ clearance are present in individuals living with AD. This accumulation of Aβ can lead to the formation of large aggregated amyloid plaques ‐ one of two detectable hallmarks of the disease. Aβ‐degrading enzymes (ADEs) are major players in the clearance of Aβ. Stimulating ADE activity or expression, in order to compensate for the decreased clearance in the AD phenotype, provides a promising therapeutic target. It has been reported in mice that upregulation of ADEs can reduce the levels of Aβ peptide and amyloid plaques – in some cases this led to improved cognitive function. Among several known ADEs, neprilysin (NEP), endothelin‐converting enzyme‐1 (ECE‐1), insulin degrading enzyme (IDE) and angiotensin‐1 converting enzyme (ACE) from the zinc metalloprotease family have been identified as important. These ADEs have the capacity to digest soluble Aβ which, in turn, cannot form the toxic oligomeric species. Whilst they are known for their amyloid‐degradation, they exhibit complexity through promiscuous nature and a broad range of substrates that they can degrade. This review highlights current structural and functional understanding of these key ADEs, giving some insight into the molecular interactions that leads to the hydrolysis of peptide substrates, the crucial tasks performed by them and the potential for therapeutic use in the future.

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Berberine chloride loaded nano‐PEGylated liposomes attenuates imidacloprid‐induced neurotoxicity by inhibiting NLRP3/Caspase‐1/GSDMD‐mediated pyroptosis

El Gazzar,

Farag,

Samir

et al. 2024

BioFactors

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Concerns have been expressed about imidacloprid (IMI), one of the most often used pesticides, and its potential neurotoxicity to non‐target organisms. Chronic neuroinflammation is central to the pathology of several neurodegenerative disorders. Hence, exploring the molecular mechanism by which IMI would trigger neuroinflammation is particularly important. This study examined the neurotoxic effects of oral administration of IMI (45 mg/kg/day for 30 days) and the potential neuroprotective effect of berberine (Ber) chloride loaded nano‐PEGylated liposomes (Ber‐Lip) (10 mg/kg, intravenously every other day for 30 days) using laboratory rat. The histopathological changes, anti‐oxidant and oxidative stress markers (GSH, SOD, and MDA), proinflammatory cytokines (IL1β and TNF‐α), microglia phenotype markers (CD86 and iNOS for M1; CD163 for M2), the canonical pyroptotic pathway markers (NLRP3, caspase‐1, GSDMD, and IL‐18) and Alzheimer's disease markers (Neprilysin and beta amyloid [Aβ] deposits) were assessed. Oral administration of IMI resulted in apparent cerebellar histopathological alterations, oxidative stress, predominance of M1 microglia phenotype, significantly upregulated NLRP3, caspase‐1, GSDMD, IL‐18 and Aβ deposits and significantly decreased Neprilysin expression. Berberine reduced the IMI‐induced aberrations in the measured parameters and improved the IMI‐induced histopathological and ultrastructure alterations brought on by IMI. This study highlights the IMI neurotoxic effect and its potential contribution to the development of Alzheimer's disease and displayed the neuroprotective effect of Ber‐Lip.

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Blood–brain barrier penetrating neprilysin degrades monomeric amyloid-beta in a mouse model of Alzheimer’s disease

Cited by 17 publications

References 70 publications

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

Molecular basis of selective amyloid‐β degrading enzymes in Alzheimer's disease

Berberine chloride loaded nano‐PEGylated liposomes attenuates imidacloprid‐induced neurotoxicity by inhibiting NLRP3/Caspase‐1/GSDMD‐mediated pyroptosis

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