scholarly journals Pharmacological inhibition of asparaginyl endopeptidase by δ-secretase inhibitor 11 mitigates Alzheimer’s disease-related pathologies in a senescence-accelerated mouse model

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Ju Wang ◽  
Hui-Jie Hu ◽  
Zi-Kai Liu ◽  
Jing-Jing Liu ◽  
Shan-Shan Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Enzymatic Activity ◽  
Mouse Brain ◽  
Pharmacological Inhibition ◽  
Asparaginyl Endopeptidase ◽  
Samp8 Mouse ◽  
Secretase Inhibitor ◽  
The Brain ◽  
Senescence Accelerated Mouse

Abstract Background Currently, there is no cure for Alzheimer’s disease (AD). Therapeutics that can modify the early stage of AD are urgently needed. Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase (AEP). Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD. However, more than 90% of AD cases are age-related sporadic AD rather than hereditary AD. The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown. Methods The senescence-accelerated mouse prone 8 (SAMP8) was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,: δ-secretase inhibitor 11. Activation of AEP was determined by enzymatic activity assay. Concentration of soluble amyloid β (Aβ) in the brain was determined by ELISA. Morris water maze test was performed to assess the learning and memory-related cognitive ability. Pathological changes in the brain were explored by morphological and western blot analyses. Results The enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the age-matched SAMR1 mice. The half maximal inhibitory concentration (IC50) for δ-secretase inhibitor 11 to inhibit AEP in vitro is was around 150 nM. Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity, reduced the generation of Aβ1–40/42 and ameliorated memory loss. The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation, but also attenuated neuroinflammation in the form of microglial activation. Moreover, treatment with δ-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain. Conclusions Pharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD. The up-regulated AEP in the brain could be a promising target for early treatment of AD. The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.

scholarly journals Trimethylamine N-Oxide (TMAO) links peripheral insulin resistance and cognitive deficiencies in a senescence accelerated mouse model

2021 ◽  
Author(s):  
Manuel H. Janeiro ◽  
Elena Puerta ◽  
Maria Lanz ◽  
Fermin I. Milagro ◽  
Maria J Ramirez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Insulin Signaling ◽  
Samp8 Mouse ◽  
Cognitive Deficiencies ◽  
Samp8 Mice ◽  
The Brain ◽  
Senescence Accelerated Mouse

It has been established that ageing is the major risk factor for cognitive deficiency or neurodegenerative diseases such as Alzheimer's disease (AD) and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. The dysfunction of the insulin signaling system and glucose metabolism has been proposed to be responsible for brain aging. Normal insulin signaling in the brain is required to mediate growth, metabolic functions, and the survival of neurons and glia. Insulin receptors are densely expressed in the olfactory bulb, the cerebral cortex and the hippocampus and regulate neurotransmitter release and receptor recruitment. In normal elderly individuals, reduced glucose tolerance and decreased insulin levels in the aged brain are typically observed. Furthermore, insulin signaling is aberrantly activated in the AD brain, leading to non-responsive insulin receptor signaling. The senescence accelerated mouse (SAMP8) mouse was one of the accelerated senescence strains that spontaneously developed from breeding pairs of the AKR/J series. The SAMP8 mouse develops early learning and memory deficits (between 6 and 8 months) together with other characteristics similar to those seen in Alzheimer's disease. The present project proposes the investigation of the missing link between aging, insulin resistance and dementia. Peripheral but not central insulin resistance was found in SAMP8 mice accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state (i.e. significantly higher adipose tissue TNF-[alpha]; and IL6 levels) were observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across a aging-disrupted BBB. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment inhibits the transformation of choline, carnitine and crotonobetaine, decreaseing TMAO levels. The ever-increasing incidence of neurodegenerative diseases not only limits the life quality of the affected individuals and their families but also poses an enormous demand on the societies. Thus, it is instrumental to pursue novel promising approaches to prevent and treat it at the highest possible speed to rapidly translate them to clinical practice. From this point of view, data obtained from this project will be instrumental to validate the principle approach of microbial dysbiosis and increased TMAO secretion as a key link between aging, insulin resistance and dementia. Collectively, the proposed experiments ideally integrate the aim to promote a novel approach to improve the lives of those suffering from cognitive disturbances.

scholarly journals Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer’s disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shan-Shan Wang ◽  
Zi-Kai Liu ◽  
Jing-Jing Liu ◽  
Qing Cheng ◽  
Yan-Xia Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Senile Plaques ◽  
Disease Stage ◽  
Assay Method ◽  
Imaging Probe ◽  
Asparaginyl Endopeptidase ◽  
Potential Biomarker ◽  
The Brain

Abstract Background Discovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology. Results This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice. Conclusions The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD. Graphical abstract

scholarly journals MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Charis Ringland ◽  
Jonas Elias Schweig ◽  
Maxwell Eisenbaum ◽  
Daniel Paris ◽  
Ghania Ait-Ghezala ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Recognition Memory ◽  
Spatial Learning ◽  
Gene Deletion ◽  
Social Recognition ◽  
Pharmacological Inhibition ◽  
Neurobehavioral Deficits ◽  
The Brain ◽  
Social Recognition Memory

Abstract Background Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer’s disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulating MMP9 activity in the brain than other apoE isoforms, and that MMP9 inhibition facilitated beta-amyloid (Aβ) elimination across the blood–brain barrier (BBB) Methods In the current studies, we evaluated the impact of MMP9 modulation on Aβ disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD) Results Treatment with the MMP9 inhibitor SB-3CT in E4FAD mice led to reduced anxiety compared to placebo using the elevated plus maze. Deletion of the MMP9 gene in 5xFAD mice also reduced anxiety using the open field test, in addition to improving sociability and social recognition memory, particularly in male mice, as assessed through the three-chamber task, indicating certain behavioral alterations in AD may be mediated by MMP9. However, neither pharmacological inhibition of MMP9 or gene deletion of MMP9 affected spatial learning or memory in the AD animals, as determined through the radial arm water maze. Moreover, the effect of MMP9 modulation on AD neurobehavior was not due to changes in Aβ disposition, as both brain and plasma Aβ levels were unchanged in the SB-3CT-treated E4FAD animals and MMP9KO/AD mice compared to their respective controls. Conclusions In total, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aβ tissue levels in AD animals. While targeting MMP9 may represent a therapeutic strategy to mitigate aspects of neurobehavioral decline in AD, further work is necessary to understand the nature of the relationship between MMP9 activity and neurological dysfunction.

scholarly journals An isogenic panel of single App knock-in mouse models of Alzheimer's disease confers differential profiles of β-secretase inhibition and endosomal abnormalities

2021 ◽  
Author(s):  
Naoto Watamura ◽  
Kaori Sato ◽  
Gen Shiihashi ◽  
Ayami Iwasaki ◽  
Naoko Kamano ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
The Arctic ◽  
Secretase Inhibitor ◽  
Beta Secretase ◽  
Abeta Production ◽  
The Brain ◽  
Experimental Comparisons

We previously developed single App knock-in mouse models of Alzheimer's disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice). These models showed the development of amyloid We previously developed single App knock-in mouse models of AD that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice). We have now generated App knock-in mice devoid of the Swedish mutations (AppG-F mice) and some additional mutants to address the following two questions: [1] Do the Swedish mutations influence the mode of beta-secretase inhibitor action in vivo? [2] Does the quantity of C-terminal fragment of amyloid precursor protein (APP) generated by beta-secretase (CTF-beta) affect endosomal properties as previously reported as well as other pathological events? Abeta pathology was exhibited by AppG-F mice from 6 to 8 months of age, and was accompanied by microglial and astrocyte activation. We found that a beta-secretase inhibitor, verubecestat, inhibited Abeta production in AppG-F mice, but not in AppNL-G-F mice, indicating that the AppG-F mice are more suitable for preclinical studies of beta-secretase inhibition given that most AD patients do not carry Swedish mutations. We also found that the quantity of CTF-beta generated by various App knock-in mutants failed to correlate with endosomal alterations or enlargement, implying that CTF-beta, endosomal abnormalities, or both are unlikely to play a major role in AD pathogenesis. This is the first AD mouse model ever described that recapitulates amyloid pathology in the brain without the presence of Swedish mutations and without relying on the overexpression paradigm. Thus, experimental comparisons between different App knock-in mouse lines will potentially provide new insights into our understanding of the etiology of AD.

Molecular cloning, expression, and regulation of hippocampal amyloid precursor protein of senescence accelerated mouse (SAMP8)

2001 ◽  
Vol 79 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Vijaya B Kumar ◽  
Kamlesh Vyas ◽  
Mark Franko ◽  
Veena Choudhary ◽  
Chakradhar Buddhiraju ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acid ◽  
Amyloid Precursor Protein ◽  
Molecular Probes ◽  
Precursor Protein ◽  
Single Amino Acid ◽  
Dependent Manner ◽  
Samp8 Mouse ◽  
Senescence Accelerated Mouse

Alzheimer's disease (AD) is associated with increased expression of amyloid precursor protein (APP) with a consequent deposition of amyloid beta peptide (Aβ) which forms characteristic senile plaques. We have noticed that the senescence accelerated mouse (SAMP8), a strain of mouse that exhibits age-dependent defects such as loss of memory and retention at an early age of 8-12 months, also produces increased amounts of APP and Aβ similar to those observed in Alzheimer's disease (AD). In order to investigate if this is due to mutations in APP similar to those observed in AD, and to develop molecular probes that regulate its expression, APP cDNA was cloned from the hippocampus of 8-month-old SAMP8 mouse. The nucleotide sequence is 99.7% homologous with that of mouse and rat, 88.7% with monkey, and 89.2% with human homologues. At the amino acid level, the homology was 99.2% and 97.6% with rodent and primate sequences, respectively. A single amino acid substitution of Alanine instead of Valine at position 300 was unique to SAMP8 mouse APP. However, no mutations similar to those reported in human familial AD were observed. When the cDNA was expressed in HeLa cells, glycosylated mature APP could be detected by immunoblotting technique. The expression could be regulated in a time- and concentration-dependent manner by using an antisense oligonucleotide specific to APP mRNA. Such regulation of APP expression may have a therapeutic application in vivo.Key words: cloning, amyloid precursor protein, transfection, expression, and antisense oligo.

Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽  
2012 ◽  
Vol 25 (4) ◽  
pp. 235-245 ◽  
Author(s):  
Katja Franke ◽  
Christian Gaser
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Aging ◽  
Brain Aging ◽  
Elderly Subjects ◽  
Additional Increase ◽  
Longitudinal Changes ◽  
Novel Method ◽  
The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

The Weak Combined Magnetic Fields Reduce the Brain β-Amyloid in an Animal Model of Sporadic Alzheimer's Disease

PIERS Online ◽  
2009 ◽  
Vol 5 (4) ◽  
pp. 311-315 ◽  
Author(s):  
Natalia V. Bobkova ◽  
Vadim V. Novikov ◽  
Natalia I. Medvinskaya ◽  
Irina Yu. Aleksandrova ◽  
Eugenii E. Fesenko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Magnetic Fields ◽  
Sporadic Alzheimer’S Disease ◽  
Combined Magnetic Fields ◽  
The Brain

SPECIFIC PROPERTIES OF TUBULIN IN THE PREFRONTAL CORTEX IN CONTROL, SCHIZOPHRENIA AND VASCULAR DEMENTIA

2020 ◽  
pp. 65-71
Author(s):  
Burbaeva G.Sh. ◽  
Androsova L.V. ◽  
Vorobyeva E.A. ◽  
Savushkina O.K.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Vascular Dementia ◽  
Binding Activity ◽  
Nephelometric Method ◽  
Rate Of Polymerization ◽  
Mental Diseases ◽  
And Control ◽  
The Brain

The aim of the study was to evaluate the rate of polymerization of tubulin into microtubules and determine the level of colchicine binding (colchicine-binding activity of tubulin) in the prefrontal cortex in schizophrenia, vascular dementia (VD) and control. Colchicine-binding activity of tubulin was determined by Sherlinе in tubulin-enriched extracts of proteins from the samples. Measurement of light scattering during the polymerization of the tubulin was carried out using the nephelometric method at a wavelength of 450-550 nm. There was a significant decrease in colchicine-binding activity and the rate of tubulin polymerization in the prefrontal cortex in both diseases, and in VD to a greater extent than in schizophrenia. The obtained results suggest that not only in Alzheimer's disease, but also in other mental diseases such as schizophrenia and VD, there is a decrease in the level of tubulin in the prefrontal cortex of the brain, although to a lesser extent than in Alzheimer's disease, and consequently the amount of microtubules.

Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Reem Habib Mohamad Ali Ahmad ◽  
Marc Fakhoury ◽  
Nada Lawand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
In Vivo Studies ◽  
Key Factors ◽  
Potential Benefits ◽  
Preclinical And Clinical Studies ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

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