Dose-dependent improvements in learning and memory deficits in APPPS1-21 transgenic mice treated with the orally active Aβ toxicity inhibitor SEN1500

Lo, Adrian C.; Tesseur, Ina; Scopes, D. I. C.; Nerou, Edmund; Callaerts-Végh, Zsuzsanna; Vermaercke, Ben; Treherne, J. Mark; Strooper, Bart De; D’Hooge, Rudi

doi:10.1016/j.neuropharm.2013.08.030

Cited by 12 publications

(10 citation statements)

References 72 publications

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“…In general, these findings are in line with other studies demonstrating age-dependent spatial learning deficits in APP/PS1-mice occurring around 8/9 months (Radde et al, 2006 ; Lo et al, 2013a , b ), as well as in BDNF +/− -mice, occurring around 10–12 months (Linnarsson et al, 1997 ; Rantamäki et al, 2013 ). Interestingly, another study using a similar mouse model reported an aggravated AD pathology in the MWM by chronic BDNF reduction (Rantamäki et al, 2013 ).…”

Section: Discussionsupporting

confidence: 91%

Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model

Psotta

Rockahr

Gruss

et al. 2015

Front. Behav. Neurosci.

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There is increasing evidence that brain-derived neurotrophic factor (BDNF) plays a crucial role in Alzheimer’s disease (AD) pathology. A number of studies demonstrated that AD patients exhibit reduced BDNF levels in the brain and the blood serum, and in addition, several animal-based studies indicated a potential protective effect of BDNF against Aβ-induced neurotoxicity. In order to further investigate the role of BDNF in the etiology of AD, we created a novel mouse model by crossing a well-established AD mouse model (APP/PS1) with a mouse exhibiting a chronic BDNF deficiency (BDNF+/−). This new triple transgenic mouse model enabled us to further analyze the role of BDNF in AD in vivo. We reasoned that in case BDNF has a protective effect against AD pathology, an AD-like phenotype in our new mouse model should occur earlier and/or in more severity than in the APP/PS1-mice. Indeed, the behavioral analysis revealed that the APP/PS1-BDNF+/−-mice show an earlier onset of learning impairments in a two-way active avoidance task in comparison to APP/PS1- and BDNF+/−-mice. However in the Morris water maze (MWM) test, we could not observe an overall aggrevated impairment in spatial learning and also short-term memory in an object recognition task remained intact in all tested mouse lines. In addition to the behavioral experiments, we analyzed the amyloid plaque pathology in the APP/PS1 and APP/PS1-BDNF+/−-mice and observed a comparable plaque density in the two genotypes. Moreover, our results revealed a higher plaque density in prefrontal cortical compared to hippocampal brain regions. Our data reveal that higher cognitive tasks requiring the recruitment of cortical networks appear to be more severely affected in our new mouse model than learning tasks requiring mainly sub-cortical networks. Furthermore, our observations of an accelerated impairment in active avoidance learning in APP/PS1-BDNF+/−-mice further supports the hypothesis that BDNF deficiency amplifies AD-related cognitive dysfunctions.

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Section: Discussionsupporting

confidence: 91%

Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model

Psotta

Rockahr

Gruss

et al. 2015

Front. Behav. Neurosci.

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“…This first of all confirms the value of MWM reversal procedures to detect subtle cognitive changes such as those following mPFC lesions6566, but also shows that mPFC is specifically involved in tasks that require the adjustment of previously learned contingencies and cognitively demanding search strategies. Defects in the deployment of spatial strategies have been described in other brain disease models as well676869, whereas rigidity in the deployment of efficient strategies to locate the hidden platform appear to underlie the presently observed impairments. Mice with mPFC lesions were unable to adjust their spatial maps and search strategies, and rather relied on a mixture of different non-spatial and repetitive strategies.…”

Section: Discussionmentioning

confidence: 93%

Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity

Latif‐Hernandez

Shah

Ahmed

et al. 2016

Sci Rep

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Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration.

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“…Aβ pathology was improved significantly in all studies with the exception of Lo et al . who experience no change following intervention. Ramalho et al .…”

Section: Resultsmentioning

confidence: 99%

“…Generally, cognition was improved by many of the agents for the emerging targets. Of the 19 studies that investigated the effects of their agent on cognition, only two reported that there were no changes in cognition , and 10 reported significant changes demonstrating an improvement across all drug classes .…”

Section: Discussionmentioning

confidence: 99%

Emerging drug targets for Aβ and tau in Alzheimer's disease: a systematic review

West

Bhugra

2015

Brit J Clinical Pharma

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Aims Currently, treatment for Alzheimer's disease (AD) focuses on the cholinergic hypothesis and provides limited symptomatic effects. Research currently focuses on other factors that are thought to contribute to AD development such as tau proteins and Aβ deposits, and how modification of the associated pathology affects outcomes in patients. This systematic review summarizes and appraises the evidence for the emerging drugs affecting Aβ and tau pathology in AD. Methods A comprehensive, systematic online database search was conducted using the databases ScienceDirect and PubMed to include original research articles. A systematic review was conducted following a minimum set of standards, as outlined by The PRISMA Group . Specific inclusion and exclusion criteria were followed and studies fitting the criteria were selected. No human trials were included in this review. In vitro and in vivo AD models were used to assess efficacy to ensure studied agents were emerging targets without large bodies of evidence. Results The majority of studies showed statistically significant improvement (P < 0.05) of Aβ and/or tau pathology, or cognitive effects. Many studies conducted in AD animal models have shown a reduction in Aβ peptide burden and a reduction in tau phosphorylation post‐intervention. This has the potential to reduce plaque formation and neuronal degeneration. Conclusions There are many emerging targets showing promising results in the effort to modify the pathological effects associated with AD. Many of the trials also provided evidence of the clinical effects of such drugs reducing pathological outcomes, which was often demonstrated as an improvement of cognition.

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Dose-dependent improvements in learning and memory deficits in APPPS1-21 transgenic mice treated with the orally active Aβ toxicity inhibitor SEN1500

Cited by 12 publications

References 72 publications

Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model

Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model

Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity

Emerging drug targets for Aβ and tau in Alzheimer's disease: a systematic review

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