Neural network dysfunction may play an important role in Alzheimer's disease (AD). Neuronal circuits vulnerable to AD are also affected in human amyloid precursor protein (hAPP) transgenic mice. hAPP mice with high levels of amyloid-beta peptides in the brain develop AD-like abnormalities, including cognitive deficits and depletions of calcium-related proteins in the dentate gyrus, a region critically involved in learning and memory. Here, we report that hAPP mice have spontaneous nonconvulsive seizure activity in cortical and hippocampal networks, which is associated with GABAergic sprouting, enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus. Many Abeta-induced neuronal alterations could be simulated in nontransgenic mice by excitotoxin challenge and prevented in hAPP mice by blocking overexcitation. Aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to Abeta-induced neurological deficits in hAPP mice and, possibly, also in humans with AD.

SUMMARY Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. To identify such mechanisms, we studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuron-specific and PV cell–predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD.

In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.epilepsy | plasticity | therapy | dementia | hyperexcitability

We show that a natural behavior, exploration of a novel environment, causes DNA double-strand breaks (DSBs) in neurons of young adult wildtype mice. DSBs occurred in multiple brain regions, were most abundant in the dentate gyrus, which is involved in spatial learning and memory, and were repaired within 24 hours. Increasing neuronal activity by sensory or optogenetic stimulation increased neuronal DSBs in relevant but not irrelevant networks. Human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of Alzheimer's disease, had increased neuronal DSBs at baseline and more severe and prolonged DSBs after exploration. Interventions that suppress aberrant neuronal activity and improve memory in hAPP mice normalized their levels of DSBs. Blocking extrasynaptic NMDA-type glutamate receptors prevented amyloid-β (Aβ)-induced DSBs in neuronal cultures. Thus, transient increases in neuronal DSBs occur as a result of physiological brain activity and Aβ exacerbates DNA damage, most likely by eliciting synaptic dysfunction.

Amyloid-β oligomers may cause cognitive deficits in Alzheimer's disease by impairing neuronal NMDA-type glutamate receptors, whose function is regulated by the receptor tyrosine kinase EphB2. Here we show that amyloid-β oligomers bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer's disease and related models, we used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centres of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation in the dentate gyrus, which are important for memory formation. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, depletion of EphB2 is critical in amyloid-β-induced neuronal dysfunction. Increasing EphB2 levels or function could be beneficial in Alzheimer's disease.Soluble amyloid-β oligomers may contribute to learning and memory deficits in Alzheimer's disease by inhibiting NMDA-receptor-dependent long-term potentiation (LTP)1 -3, thought to underlie memory formation4. In Alzheimer's disease, hippocampal NMDA-receptorsubunit levels are reduced5, and protein levels and the phosphorylation status of NMDAreceptor subunits NR1, NR2A and NR2B correlate with cognitive performance6. Human amyloid precursor protein (hAPP) transgenic mice with high brain levels of amyloid-β oligomers have reduced hippocampal levels of tyrosine-phosphorylated NMDA receptors and key components of NMDA-receptor-dependent signalling pathways7 , 8. Alzheimer's disease patients and hAPP mice have hippocampal depletions of the receptor tyrosine kinase EphB29, which regulates NMDA-receptor trafficking and function by interacting with NMDA receptors and Src-mediated tyrosine phosphorylation10 -13. EphB2 regulates NMDA-receptor-dependent Ca 2+ influx and downstream transcription factors involved in LTP formation12, such as Fos, which is depleted in the dentate gyrus of hAPP mice. Mice lacking EphB210 , 14 or Fos15 have impaired NMDA-receptor-dependent LTP and memory deficits. We hypothesized that EphB2 depletion in Alzheimer's disease-related models is caused by amyloid-β oligomers and that reductions in EphB2 contribute to amyloid-β-induced deficits in synaptic plasticity and cognitive functions (Supplementary Fig. 1). Here NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2011 July 6. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptwe confirm these hypotheses and show that reversing EphB2 depletion in the dentate gyrus of hAPP mice reverses LTP and memory impairments. Amyloid-β oligomers bind to EphB2To determine if amyloid-β oligomers interact directly with EphB2, we measured binding of biotinylated synthetic amyloid-β1-42 oligomers to a purified recombinant Ep...