Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease

Busche, Marc Aurel; Eichhoff, Gerhard; Adelsberger, Helmuth; Abramowski, Dorothée; Wiederhold, Karl‐Heinz; Haass, Christian; Staufenbiel, Matthias; Konnerth, Arthur; Garaschuk, Olga

doi:10.1126/science.1162844

Cited by 942 publications

(1,060 citation statements)

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“…In this study, we used 6-to 8-mo-old APP23xPS45 transgenic mice that exhibit severe cerebral Aβ pathology, neuritic and glial cytopathology, and learning and memory deficits (10,11). In accordance with a previous protocol (9), we treated the plaque-bearing mice for 6-8 wk with food pellets containing the BACE inhibitor NB-360 (0.25 mg/g of food, corresponding to a daily oral dose of 20 μmol/kg) or control pellets without the inhibitor.…”

Section: Resultsmentioning

confidence: 99%

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BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Keskin

Kekuš

Adelsberger

et al. 2017

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

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107

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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: Resultsmentioning

confidence: 99%

“…To assess whether the treatment with NB-360 had any beneficial effects on learning and memory deficits in the aged transgenic mice, we trained mice in a water maze task to find a fixed, visible platform (10,11) (Fig. 4A).…”

Section: Significancementioning

confidence: 99%

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Keskin

Kekuš

Adelsberger

et al. 2017

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

Self Cite

107

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“…We report here a third system involving presynaptic neurons. Presynaptic neuronal Ca 2+ hyperactivation has been reported to occur near amyloid plaques in AD model mice (44). Interestingly, such hyperactivation of neurons in hippocampus has been associated with the cortical thinning in mild cognitive impairment patients and has been considered to be an early indicator of AD-related neurodegeneration (45).…”

Section: Discussionmentioning

confidence: 99%

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Ohnishi

Yanazawa

Sasahara

et al. 2015

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

116

155

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Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10-to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuronspecific Na + /K + -ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aβ-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn 879 and Trp 880 is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.NMR | computational modeling | abnormal protein-protein interaction in synapse | hyperexcitotoxicity | protein-protein interaction inhibitors

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“…CTF, C terminal fragment; sAPP, soluble APP; BACE, b-site APP cleavage enzyme, ADAM, a disintegrin and metalloprotease, TACE, tumor necrosis factor a cleavage enzyme; Aph1, anterior pharynx defective; Pen, presenilin enhancer. plaques found that excitability was increased in the areas of cortex adjacent to plaques relative to areas further away (37,38). However, more research is needed before it can be concluded that Ab plaque is responsible for seizures.…”

Section: Pass the Salt: Mechanisms Of Seizures In Mouse Models Of Ad mentioning

confidence: 99%

“Untangling” Alzheimer's Disease and Epilepsy

Scharfman

2012

Epilepsy Curr

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There is a substantial body of evidence that spontaneous recurrent seizures occur in a subset of patients with Alzheimer disease (AD), especially the familial forms that have an early onset. In transgenic mice that simulate these genetic forms of AD, seizures or reduced seizure threshold have also been reported. Mechanisms underlying the seizures or reduced seizure threshold in these mice are not yet clear and are likely to be complex, because the synthesis of amyloid β (Aβ) involves many peptides and proteases that influence excitability. Based on transgenic mouse models of AD where Aβ and its precursor are elevated, it has been suggested that seizures are caused by the downregulation of the Nav1.1 sodium channel in a subset of GABAergic interneurons, leading to a reduction in GABAergic inhibition. Another mechanism of hyperexcitability appears to involve tau, because deletion of tau reduces seizures in some of the same transgenic mouse models of AD. Therefore, altered excitability may be as much a characteristic of AD as plaques and tangles—especially for the familial forms of AD.

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Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease

Cited by 942 publications

References 40 publications

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

“Untangling” Alzheimer's Disease and Epilepsy

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