Alzheimer’s disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn.Weshowed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded whole cell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit.

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...

Neuronal expression of familial Alzheimer's disease (AD)-mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-β (Aβ) peptides causes synaptic dysfunction, inflammation, and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to AD pathogenesis is uncertain. A lipidomics approach to broadly profile fatty acids in brain tissues of hAPP mice revealed an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A2 (GIVA-PLA2). Levels of activated GIVA-PLA2 in the hippocampus were increased in AD patients and hAPP mice. Aβ caused a dose-dependent increase in GIVA-PLA2 phosphorylation in neuronal cultures. Inhibition of GIVA-PLA2 diminished Aβ-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA2 protected hAPP mice against Aβ-dependent deficits in learning and memory, behavioral alterations, and premature mortality. Inhibition of GIVA-PLA2 may be of benefit in the treatment and prevention of AD.

SUMMARY The entorhinal cortex (EC) is one of the earliest affected and most vulnerable brain regions in Alzheimer’s disease (AD), which is associated with amyloid-β (Aβ) accumulation in many brain areas. We show selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC causes cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP overexpression, including hyperactivity, disinhibition, and spatial learning and memory deficits. Overexpression of APP/Aβ in the EC elicited abnormalities in synaptic functions and activity-related molecules in the dentate gyrus and CA1, as well as epileptiform activity in parietal cortex. Soluble Aβ was observed in the dentate gyrus and Aβ deposits in the hippocampus were localized to perforant pathway terminal fields. Thus, APP/Aβ expression in EC neurons can cause transsynaptic deficits, which could initiate the cortical-hippocampal network dysfunction observed in mouse models and human patients with AD.