Characterizing the Appearance and Growth of Amyloid Plaques in APP/PS1 Mice

Yan, Ping; Bero, Adam W.; Cirrito, John R.; Xiao, Qingli; Hu, Xiaoyan; Wang, Yan; Gonzales, Ernesto R.; Holtzman, David M.; J, Lee

doi:10.1523/jneurosci.2637-09.2009

Cited by 239 publications

(219 citation statements)

References 49 publications

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“…Our results further suggest that neuronal hyperactivity within amyloid plaque-bearing local circuits is likely due to prefibrillary Aβ species, which form a halo around the plaque cores. The findings are unexpected in view of previous evidence indicating that at such advanced disease stages, many pathological and cellular processes are chronic and mostly irreversible (7,8,(23)(24)(25). In fact, we found that most dysfunctional neurons in the amyloid-plaque bearing neocortex are still viable, and that their "hyperactive phenotype" can be reversed by reducing Aβ in the brain.…”

Section: Discussioncontrasting

confidence: 90%

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Keskin

Kekuš

Adelsberger

et al. 2017

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

111

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Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca 2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.A lzheimer´s disease (AD) is the most common cause of dementia globally, with an increasing impact on aging societies (1). Therefore, the prevention and treatment of AD is a major unmet medical need. The amyloid hypothesis posits that the abnormal accumulation of amyloid-β (Aβ) peptides in the brain, and their aggregation, is an essential feature of AD (2, 3); however, results from clinical studies using several Aβ-targeting compounds have called into question the existence of a direct link between a reduction in Aβ and improvement of brain function, particularly in more advanced disease stages (4-6). In addition, recent evidence obtained in mouse models carrying genetic mutations that cause AD in humans revealed that immunotherapy with antibodies against Aβ worsened rather than reversed neuronal dysfunction (7). Despite reducing plaque burden, the anti-Aβ antibodies caused a massive increase in cortical hyperactivity and promoted abnormal synchrony of neurons in a subset of the treated mice. In this context, it is noteworthy that another recent mouse study found an increased risk of sudden death after anti-Aβ antibody treatment, which was attributed to enhanced excitatory neuronal activity culminating in fatal convulsive seizures (8).To clarify the causal relationship between Aβ and pathophysiology in vivo, we made use of a novel compound that reduces Aβ by inhibiting the β-secretase BACE, the rate-limiting enzyme for Aβ production (9). This approach allowed us to determine how the inhibition of Aβ production affects neural circuit and memory impairments in APP23xPS45 transgenic mice overexpressing mutant human amyloid precursor protein (APP) and presenilin 1 (PS1). The combination of histochemistry, in vivo Ca 2+ imaging, and behavioral analysis allowed us to directly link the treatment-related changes in brain Aβ levels to changes in neuronal and cognitive functions in individual mice. ResultsIn this study, we used 6-to 8-mo-old APP23xPS45 transgenic mice that exhibit severe cerebral Aβ pathology, neur...

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Section: Discussioncontrasting

confidence: 90%

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Keskin

Kekuš

Adelsberger

et al. 2017

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

111

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“…3). In in vivo model systems, similar magnitudes of Aβ reductions are sufficient to prevent or halt Aβ plaque accumulation (53,54).…”

Section: Discussionmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

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

314

307

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Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonindependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.microdialysis | selective serotonin reuptake inhibitor antidepressants | late-life depression A myloid-β (Aβ) dysregulation appears to initiate the pathogenesis of Alzheimer's disease (AD) with a cascade of downstream factors that exacerbate and propagate neuronal injury (1). Aβ can accumulate as toxic plaques and soluble oligomers in the brains of individuals with AD a decade or more before the initial symptoms are identified (2). The concentration of Aβ is a critical factor determining if and when it will aggregate into these toxic structures; high concentrations of Aβ are more prone to convert from its normal soluble form into these multimeric conformations (3). Aβ is formed within neurons by sequential cleavage of the amyloid precursor protein (APP) by two enzymes, β-secretase and then γ-secretase. Alternatively, α-secretase can cleave APP within the Aβ sequence, which precludes the peptide from being formed at all. The enzymes and mechanisms that produce Aβ have been well characterized; however, the mechanisms that regulate Aβ production and levels are only partly understood. Understanding the cellular processes that regulate Aβ levels may provide greater insight into disease pathogenesis and suggest new avenues to treat or prevent AD.Synaptic activity is one key regulator of brain Aβ production. Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracel...

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“…Female transgenic mice were used because female mice manifest an early deficit in spatial memory in the MWM test and develop greater Aβ burden compared to age‐matched male mice (Gallagher et al ., 2013). The 4.5‐month‐old mice were selected because this transgenic line develops amyloid plaque by 4–6 months of age (Yan et al ., 2009), and memory deficits as early as 6 months of age by contextual fear conditioning test (Kilgore et al ., 2010). The 4.5‐month‐old mice are suitable for investigating the effect of intranasal insulin on early Aβ pathology.…”

Section: Methodsmentioning

confidence: 99%

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

et al. 2016

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SummaryBrain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β‐amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5‐month‐old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c‐Jun N‐terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

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Characterizing the Appearance and Growth of Amyloid Plaques in APP/PS1 Mice

Cited by 239 publications

References 49 publications

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

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