Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model

Sanchez, Pascal; Zhu, Lei; Verret, Laure; Vossel, Keith A.; Orr, Anna G.; Cirrito, John R.; Devidze, Nino; Ho, Kaitlyn; Gui, Yu; Palop, Jorge J.; Mucke, Lennart

doi:10.1073/pnas.1121081109

Cited by 566 publications

(615 citation statements)

References 70 publications

(80 reference statements)

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“…A recent clinical study of AD patients has revealed that convulsive seizures occurred early in the course of AD, which often began around the same time when symptoms of neurodegeneration first appeared (55). Levetiracetam, which inhibits presynaptic calcium channels (56), suppresses neuronal hyperactivation, and reverses cognitive deficits in their AD model mice (57). These results are consistent with our findings (Fig.…”

Section: Discussionsupporting

confidence: 83%

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.

119

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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Section: Discussionsupporting

confidence: 83%

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.

119

155

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“…Consistent with the effects of hTau‐A152T and hTau‐WT on evoked and spontaneous epileptic activity, expression of either hTau species enhanced the increased risk of early death in hAPP mice, which have epileptiform activity even in the absence of hTau overexpression 46, 49. hTau‐A152T was more detrimental in this regard than hTau‐WT.…”

Section: Discussionsupporting

confidence: 56%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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A152T‐variant human tau (hTau‐A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau‐A152T or wild‐type hTau (hTau‐WT), we find age‐dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau‐A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau‐A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau‐A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co‐expression of hTau‐A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau‐A152T and amyloid‐β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.

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“…The two diseases also exhibit significant comorbidity 51 . An antiepileptic drug (levetiracetam) was recently found to reverse deficits in learning and memory in AD mice and might also help ameliorate related abnormalities in human 52 . Symptoms represent the high-level manifestations of a disease that are actually observed by patients and physicians.…”

Section: Discussionmentioning

confidence: 99%

Human symptoms–disease network

Zhou¹,

Menche²,

Barabási³

et al. 2014

Nat Commun

600

484

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In the post-genomic era, the elucidation of the relationship between the molecular origins of diseases and their resulting phenotypes is a crucial task for medical research. Here, we use a large-scale biomedical literature database to construct a symptom-based human disease network and investigate the connection between clinical manifestations of diseases and their underlying molecular interactions. We find that the symptom-based similarity of two diseases correlates strongly with the number of shared genetic associations and the extent to which their associated proteins interact. Moreover, the diversity of the clinical manifestations of a disease can be related to the connectivity patterns of the underlying protein interaction network. The comprehensive, high-quality map of disease-symptom relations can further be used as a resource helping to address important questions in the field of systems medicine, for example, the identification of unexpected associations between diseases, disease etiology research or drug design.

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Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model

Cited by 566 publications

References 70 publications

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

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

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Human symptoms–disease network

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