Memantine Improves Cognition and Reduces Alzheimer’s-Like Neuropathology in Transgenic Mice

Martínez-Coria, Hilda; Green, Kim N.; Billings, Lauren M.; Kitazawa, Masashi; Albrecht, Miriam; Rammes, Gerhard; Parsons, Chris G.; Gupta, Sandeep; Banerjee, Pradeep; LaFerla, Frank M.

doi:10.2353/ajpath.2010.090452

Cited by 194 publications

(137 citation statements)

References 55 publications

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“…In contrast, with such a short period of treatment Mem was unable to improve the memory-loss phenotype ( Fig. 2E), although it was reported to be effective with much longer treatment times (32,34). Effects of Ge were also consistent in the plot of representative paths ( Fig.…”

Section: Ameliorating Aβ42-induced Memory Loss By Inhibition Of Egfrs Insupporting

confidence: 58%

“…In the current study, behavior results of Ge treatments in the mouse model contrasted sharply with those of Mem, which had no memory-rescuing effects with the short-period treatment. However, in other reports, Mem was effective after oral administration for several months (32,34). We also noted that treating APP/PS1 mice with Ge for 18 d did not significantly influence the Aβ aggregation (oligomers and amyloid plaques) level in the brain (Fig.…”

Section: Discussionmentioning

confidence: 78%

“…The Morris water maze was performed as in previous reports (30,32). A water tank (120 cm in diameter) was filled with roomtemperature water (19-20°C) that was made opaque with milk.…”

Section: Methodsmentioning

confidence: 99%

“…Extensive plaques are reported to be visible in early ages and the memory-loss phenotype is evident around 6-9 mo of age in double transgenic mice (27)(28)(29)(30)(31). The Morris water maze was used for the behavioral assay, in which mice learned to find a hidden platform (32). For drug treatment, we chose a very short period of feeding paradigm, including only a 7-d pretesting drug treatment followed with a 2-d adaption to the water maze environment and then 9 d of training and testing ( Fig.…”

Section: Ameliorating Aβ42-induced Memory Loss By Inhibition Of Egfrs Inmentioning

confidence: 99%

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Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory loss

Wang

Chiang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

158

141

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Current understanding of amyloid-β (Aβ) metabolism and toxicity provides an extensive list of potential targets for developing drugs for treating Alzheimer's disease. We took two independent approaches, including synaptic-plasticity-based analysis and behavioral screening of synthetic compounds, for identifying single compounds that are capable of rescuing the Aβ-induced memory loss in both transgenic fruit fly and transgenic mouse models. Two clinically available drugs and three synthetic compounds not only showed positive effects in behavioral tests but also antagonized the Aβ oligomers-induced activation of the epidermal growth factor receptor (EGFR). Such surprising converging outcomes from two parallel approaches lead us to conclude that EGFR is a preferred target for treating Aβ-induced memory loss.A myloid-β (Aβ) oligomers-induced memory loss is thought to be a hallmark of Alzheimer's disease (AD) progression (1-3). Aβ peptides are cleaved from a membrane protein APP via β-and γ-secretases' activities (4). They can be removed through activities of neprilysin, insulin-degradation enzyme, and possibly other mechanisms (5-7). Aβ is also able to bind with a large array of target proteins, such as EphB2, TNF-R1, RAGE1, and NMDA receptor and prion (8)(9)(10)(11)(12) to exert a wide range of effects, including synaptic transmission, protein transportation, mitochondrial functions, and others (13-15). Thus, there are a large number of potential targets for developing AD treatment based on the Aβ hypothesis, for example, the mechanisms either reducing the production of Aβ peptides or enhancing the degradation process. It remains, however, an open question as to whether some of these targets are, at the organism level, better suited for drug development than others. One important reason is that manipulating activities of such production and degradation enzymes may affect many other physiological proteins. Thus, reported failures in a number of Aβ-based drug efforts (16) stress the necessity of identifying such preferred targets.To evaluate the possibility of finding preferred targets, we looked for overlapping and converging effects of identified targets with multiple independent approaches. First, following the direction of a synaptic-plasticity-based, mechanism-guided study, we continued to work on the signal transduction pathway of PI3-kinase that has been shown to mediate an Aβ-induced change in long-term synaptic depression as well as the Aβ-induced memory loss in Aβ42-expressing Drosophila, which recapitulates several ADlike symptoms (17). These efforts led us to find Aβ42 oligomersinduced activation of the epidermal growth factor receptor (EGFR) and the rescue of Aβ-induced memory loss in transgenic Drosophila and APP/PS1 double transgenic mouse models through treatments with clinically available EGFR inhibitors. Second, we worked to identify single compounds capable of rescuing Aβ-induced memory loss through large-scale behavioral screening with Aβ42-expressing transgenic fruit flies, followed by a confirma...

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Section: Ameliorating Aβ42-induced Memory Loss By Inhibition Of Egfrs Insupporting

confidence: 58%

Section: Discussionmentioning

confidence: 78%

“…The Morris water maze was performed as in previous reports (30,32). A water tank (120 cm in diameter) was filled with roomtemperature water (19-20°C) that was made opaque with milk.…”

Section: Methodsmentioning

confidence: 99%

Section: Ameliorating Aβ42-induced Memory Loss By Inhibition Of Egfrs Inmentioning

confidence: 99%

See 2 more Smart Citations

Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory loss

Wang

Chiang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

158

141

View full text Add to dashboard Cite

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“…161 The jury is still out on the neuroprotective potential of memantine in Alzheimer patients, 162 but laboratory evidence remains encouraging. 163 The jury has also looked hard for evidence that statin therapy prevents or ameliorates AD, but a definitive verdict is still pending. 164 Nevertheless, because there are other important reasons for the elderly to take statins, we can expect to need to anesthetize many AD patients who are on statins.…”

Section: Potential Alleviating Factorsmentioning

confidence: 99%

Developmental Disability in the Young and Postoperative Cognitive Dysfunction in the Elderly After Anesthesia and Surgery: Do Data Justify Changing Clinical Practice?

Cottrell

Hartung

2012

Mount Sinai J Medicine

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The assumption that anesthesia has no serious, long‐term, adverse central nervous system consequences may be true for most patients between 6 months and 60 years of age. However, for patients younger than 6 months or older than 60 years, that status quo assumption is under challenge from a growing body of evidence. Fetuses and newborns appear to be at risk because systems that would enable them to fully recover from the effects of more than 2 hours of anesthesia are still in development. In distinction, the elderly appear to be at risk because systems that once enabled them to fully recover have ever‐diminishing capacity. Even for those between the age of 6 months and 60 years, full recovery may require replacing apoptosed neurons and pruning overabundant dendritic spines … perhaps leaving patients not quite the same person that they were before they were anesthetized. Mt Sinai J Med 79:75–94, 2012. © 2012 Mount Sinai School of Medicine

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Animal Models of Alzheimer's Disease

Bharadwaj

2019

Neurodegeneration and Alzheimer's Disease

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Memantine Improves Cognition and Reduces Alzheimer’s-Like Neuropathology in Transgenic Mice

Cited by 194 publications

References 55 publications

Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory loss

Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory loss

Developmental Disability in the Young and Postoperative Cognitive Dysfunction in the Elderly After Anesthesia and Surgery: Do Data Justify Changing Clinical Practice?

Animal Models of Alzheimer's Disease

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