Progressive age‐related development of Alzheimer‐like pathology in APP/PS1 mice

Trinchese, Fabrizio; Liu, Shumin; Battaglia, Fortunato; Walter, Sean; Mathews, Paul M.; Arancio, Ottavio

doi:10.1002/ana.20101

Cited by 327 publications

(255 citation statements)

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“…Previous studies have reported that LTP is impaired in the hippocampus of various AD mouse models (9,(22)(23)(24). Here we used a mouse model of AD that expresses a mutated chimeric mouse/human APP and the exon-9-deleted variant of human PS1, both linked to familial AD, under the control of a prion promoter element (APPSwe/PS1dE9) (25).…”

Section: Resultsmentioning

confidence: 99%

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer’s disease

Navakkode

Rothkegel

et al. 2017

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

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Dynamic regulation of plasticity thresholds in a neuronal population is critical for the formation of long-term plasticity and memory and is achieved by mechanisms such as metaplasticity. Metaplasticity tunes the synapses to undergo changes that are necessary prerequisites for memory storage under physiological and pathological conditions. Here we discovered that, in amyloid precursor protein (APP)/presenilin-1 (PS1) mice (age 3-4 mo), a prominent mouse model of Alzheimer's disease (AD), late long-term potentiation (LTP; L-LTP) and its associative plasticity mechanisms such as synaptic tagging and capture (STC) were impaired already in presymptomatic mice. Interestingly, late long-term depression (LTD; L-LTD) was not compromised, but the positive associative interaction of LTP and LTD, cross-capture, was altered in these mice. Metaplastic activation of ryanodine receptors (RyRs) in these neurons reestablished L-LTP and STC. We propose that RyRmediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD.A lzheimer's disease (AD), the most frequent form of dementia, is an age-related neurodegenerative disorder clinically characterized by early declarative memory deficits, followed by deterioration of other cognitive functions (1). The memory loss in AD is characterized by extracellular accumulation of amyloid β protein (Aβ) in the hippocampus and cerebral cortex preceding neurodegeneration (2, 3). Increasing evidence suggests that soluble forms of Aβ interfere with hippocampal synaptic plasticity mechanisms known to mediate learning and memory processes, including long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission (4-8). In particular, the protein synthesis-dependent late phase of LTP (L-LTP) is impaired in the hippocampus of various AD transgenic mouse models and in Aβ-treated hippocampal slices (4, 9), whereas LTD is facilitated (10) or not altered (10-12). It has been reported recently that Aβ-induced inhibition of LTP is mediated by extrasynaptic NMDA receptor activity, which prevents phosphorylation of the transcription factor cAMP response element-binding protein (13,14).Synaptic plasticity can be governed by a previous activity of the same postsynaptic neuron or neural network, a phenomenon referred to as metaplasticity (15). Metaplasticity orchestrates multiple aspects of functional plasticity and thus promotes long-term memory storage (16). For instance, inducing metaplasticity by activating ryanodine (RYA) receptors (RyRs) with its agonist RYA in hippocampal CA3-CA1 synapses lowers the threshold of LTP, resulting in enhanced LTP induction and persistence (17,18). In addition, metaplasticity can influence processes of associative memory storage as in the case for synaptic tagging and capture (STC) (17). STC is defined as the associative interactions between two independent sets of synapses within the same neuronal network, in which a synaptic...

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Section: Resultsmentioning

confidence: 99%

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer’s disease

Navakkode

Rothkegel

et al. 2017

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

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“…20 The transgenic mouse model (APP/PS1) employed in this study expresses human APPs and PS1-ΔE9 and develops elevated Aβ1−42 levels at the age of 4 months with manifest plaque deposition a month later. 21 ψ-GSH (500 mg/kg ip) was administered to 3-month old APP/PS female mice three times per week for 12 consecutive weeks. Nontransgenic WT C57BL/6 mice were employed as negative controls.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Restoration of Glyoxalase Enzyme Activity Precludes Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease

Vartak

Vince

2012

ACS Chem. Neurosci.

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Pathologically high brain levels of reactive dicarbonyls such as methylglyoxal or glyoxal initiate processes that lead ultimately to neurodegeneration, presented clinically as Alzheimer’s disease and other cognitive or motor impairment disorders. Methylglyoxal and glyoxal result from glycolysis and normal metabolic pathways. Their reaction products with proteins (advanced glycation end products), and their primary chemical toxicities are both linked unequivocally to the primary pathologies of Alzheimer’s disease, namely, amyloid plaques and neurofibrillary tangles. Generation of dicarbonyls is countered through the reduction of dicarbonyls by the glutathione-dependent glyoxalase enzyme system. Although glyoxalase-I is overexpressed in early and middle stages of Alzheimer’s disease, glutathione depletion in the Alzheimer’s afflicted brain cripples its efficacy. Due to the lack of a suitable pharmacological tool, the restoration of glyoxalase enzyme activity in pre-Alzheimer’s or manifest Alzheimer’s remains yet unvalidated as a means for anti-Alzheimer’s therapy development. Disclosed herein are the results of a preclinical study into the therapeutic efficacy of ψ-GSH, a synthetic cofactor of glyoxalase, in mitigating Alzheimer’s indicators in a transgenic mouse model (APP/PS1) that is predisposed to Alzheimer’s disease. ψ-GSH administration completely averts the development of spatial mnemonic and long-term cognitive/cued-recall impairment. Amyloid β deposition and oxidative stress indicators are drastically reduced in the ψ-GSH-treated APP/PS1 mouse. ψ-GSH lacks discernible toxicity at strikingly high doses of 2000 mg/kg. The hypothesis that restoring brain glyoxalase activity would ameliorate neurogeneration stands validated, thus presenting a much needed new target for design of anti-Alzheimer’s therapeutics. Consequently, ψ-GSH is established as a candidate for drug-development.

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“…APP/PS1 mouse is a double transgenic mouse that overexpress APP together with presenilin 1 (PS1). These mice have an accelerated course of AD-like changes and currently are used by several laboratories for studies on the mechanisms of AD progression and for the development of new therapeutics (Trinchese et al, 2004). We demonstrated that social isolation rearing increases hippocampal Ab levels by increasing b-and g-secretase activities, resulting in the conversion of p35 to p25.…”

Section: Introductionmentioning

confidence: 81%

The Involvement of Cdk5 Activator p35 in Social Isolation-Triggered Onset of Early Alzheimer’s Disease-Related Cognitive Deficit in the Transgenic Mice

Hsiao

Chen

et al. 2011

Neuropsychopharmacol

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Epidemiological studies indicate that isolated persons have increased risk of developing Alzheimer's disease (AD). This study investigated the cellular mechanisms of how social isolation influenced amyloid b peptide (Ab) accumulation and affected the severity of AD-associated cognitive decline in a mouse model of AD. Amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice were placed either in isolation or in group from postnatal day 28 and tested for cognitive performance at the age of 3 months with fear-conditioning paradigms. We found that social isolation accelerated impairment of contextual fear memory in the APP/PS1 mice. The magnitude of long-term potentiation in the hippocampal CA1 neurons was significantly lower in the isolated APP/PS1 mice compared with group APP/PS1 and wild-type mice. Hippocampal level of Ab was significantly elevated in the isolated APP/PS1 mice, which was accompanied by an increased calpain activity and p25/p35 ratio. In addition, surface expression of GluR1 subunit of AMPA receptor was decreased by social isolation. The association of p35, and a-CaMKII was significantly less in the isolated APP/PS1 mice indicating that their interaction was impaired. These results suggest that social isolation exacerbates memory deficit by increasing Ab level, leading to the increased calpain activity, conversion of p35 to p25 and decrease in association of p35, a-CaMKII, and GluR1, resulting in the endocytosis of AMPA receptors.

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Progressive age‐related development of Alzheimer‐like pathology in APP/PS1 mice

Cited by 327 publications

References 69 publications

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer’s disease

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer’s disease

Restoration of Glyoxalase Enzyme Activity Precludes Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease

The Involvement of Cdk5 Activator p35 in Social Isolation-Triggered Onset of Early Alzheimer’s Disease-Related Cognitive Deficit in the Transgenic Mice

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