A pathological hallmark of Alzheimer’s disease (AD) is an accumulation of insoluble plaque containing the amyloid-β peptide (Aβ) of 40–42 aa residues1. Prefibrillar, soluble oligomers of Aβ have been recognized to be early and key intermediates in AD-related synaptic dysfunction2–9. At nanomolar concentrations, soluble Aβ-oligomers block hippocampal long-term potentiation7, cause dendritic spine retraction from pyramidal cells5,8 and impair rodent spatial memory2. Soluble Aβ-oligomers have been prepared from chemical syntheses, from transfected cell culture supernatants, from transgenic mouse brain and from human AD brain2,4,7,9. Together, these data imply a high affinity cell surface receptor for soluble Aβ-oligomers on neurons, one that is central to the pathophysiological process in AD. Here, we identify the cellular Prion Protein (PrPC) as an Aβ-oligomer receptor by expression cloning. Aβ-oligomers bind with nanomolar affinity to PrPC, but the interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the Aβ-oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent Aβ-oligomer binding to PrPC and rescue synaptic plasticity in hippocampal slices from oligomeric β. Thus, PrPC is a mediator of Aβoligomer induced synaptic dysfunction, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.

SUMMARY Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer’s disease (AD) pathophysiology. Cellular Prion Protein (PrPC) selectively binds oligomeric Aβ and can mediate AD-related phenotypes. Here, we examined the specificity, distribution and signaling from Aβ/PrP complexes, seeking to explain how they might alter the function of NMDA receptors in neurons. PrPC is enriched in post-synaptic densities, and Aβ/PrPC interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from human AD brain interact with PrPC to activate Fyn. Aβ engagement of PrPC/Fyn signaling yields phosphorylation of the NR2B subunit of NMDA-receptors, which is coupled to an initial increase and then loss of surface NMDA-receptors. Aβ-induced LDH release and dendritic spine loss require both PrPC and Fyn, and human familial AD transgene-induced convulsive seizures do not occur in mice lacking PrPC. These results delineate an Aβ oligomer signal transduction pathway requiring PrPC and Fyn to alter synaptic function with relevance to AD.

SUMMARY Soluble Amyloid-β oligomers (Aβo) trigger Alzheimer’s disease (AD) pathophysiology and bind with high affinity to Cellular Prion Protein (PrPC). At the post-synaptic density (PSD), extracellular Aβo bound to lipid-anchored PrPC activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo–PrPC with Fyn. Only co-expression of the metabotropic glutamate receptor, mGluR5, allowed PrPC-bound Aβo to activate Fyn. PrPC and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo–PrPC generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the later is also driven by human AD brain extracts. In addition, signaling by Aβo–PrPC–mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory and synapse density. Thus, Aβo–PrPC complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.

Epileptic activity is frequently associated with Alzheimer’s disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer’s disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer’s disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer’s disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer’s disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer’s disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid β and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer’s disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.

Summary A delineation of the molecular basis of synapse development is crucial for understanding brain function. Co-cultures of neurons with transfected fibroblastoid cells have been used to demonstrate the synapse-promoting activity of candidate molecules. Here, we performed an unbiased expression screen for synaptogenic proteins in the co-culture assay using custom-made full-length cDNA libraries. Re-isolation of NGL-3/LRRC4B and neuroligin-2 accounts for a minority of positive clones, indicating that current understanding of mammalian synaptogenic proteins is far from complete. We identify LRRTM1 as a novel transmembrane protein capable of inducing presynaptic differentiation in contacting axons. All four LRRTM family members exhibit synaptogenic activity, LRRTMs localize to excitatory synapses, and artificially-induced clustering of LRRTMs mediates postsynaptic differentiation in dendrites. We generate LRRTM1 -/- mice and reveal altered distribution of the vesicular glutamate transporter VGLUT1, confirming an in vivo synaptic function. These results suggest a prevalence of LRR domain proteins in trans-synaptic signaling and provide a cellular basis for the recently reported linkage of LRRTM1 to handedness and schizophrenia.

Soluble oligomers of the amyloid-β (Aβ) peptide are thought to play a key role in the pathophysiology of Alzheimer’s disease (AD). Recently, we reported that synthetic Aβ oligomers bind to cellular prion protein (PrPC) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Aβ peptide. We hypothesized that PrPC is essential for the ability of brain-derived Aβ to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1ΔE9 into Prnp−/− mice to examine the necessity of PrPC for AD-related phenotypes. Neither APP expression nor Aβ level is altered by PrPC absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrPC expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1ΔE9 transgenic mice. The AD transgenic mice with intact PrPC expression exhibit deficits in spatial learning and memory. Mice lacking PrPC, but containing Aβ plaque derived from APPswe/PSen1ΔE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrPC expression dissociates Aβ accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrPC.

Objective Currently no effective disease modifying agents exist for the treatment of AD. The Fyn tyrosine kinase is implicated in Alzheimer’s disease (AD) pathology triggered by amyloid-β oligomers (Aβo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. Methods The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aβo signaling to Fyn, Pyk2 and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, APP metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. Results AZD0530 potently inhibits Fyn and prevents both Aβo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product, Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aβ metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. Interpretation Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder. Early in the pathophysiology of AD, synaptic function is disrupted by soluble Aβ oligomers, possibly through Aβ-mediated internalization of NMDA receptors. Striatal-enriched phosphatase (STEP) is a tyrosine phosphatase that regulates the internalization of NMDA receptors. Recent work shows that STEP is elevated in the prefrontal cortex of human AD patients and in animal models of AD. Here, we use genetic manipulations to reduce STEP activity in a triple transgenic AD mouse model and show that a decrease in STEP levels reverses cognitive and cellular deficits observed in these mice. Our results suggest that STEP inhibitors may prove therapeutic for this devastating disorder.β amyloid | glutamate receptor trafficking | protein tyrosine phosphatase | long-term potentiation A lzheimer's disease (AD) is the most common form of dementia. Considerable evidence implicates β amyloid (Aβ) peptides in the pathophysiology of AD (1). Aβ 1-42 is derived from sequential cleavage of amyloid procursor protein (APP) by β-and γ-secretases. A recent hypothesis suggests that soluble Aβ oligomers disrupt synaptic and cognitive function early in the disease process (2-4). This model is supported by the findings that synaptic function is disrupted and synapses are lost early in the disorder and in animal models, even before amyloid plaques are detected (5-7). Application of soluble Aβ preparations results in synapse loss, blocks long-term potentiation (LTP), and impairs cognitive function in animals (8-11). Furthermore, animals that express high levels of Aβ show impaired synaptic plasticity and learning (6,12,13).Striatal-enriched phosphatase 61 (STEP 61 ; protein tyrosine phosphatase non-receptor 5 [PTPN5]) is a brain-specific tyrosine phosphatase targeted to synaptic compartments in striatum, hippocampus, cortex, and related brain regions (14-16). STEP 61 associates with the NMDA subclass of glutamate receptors, decreases NMDA receptor (NMDAR) activity, and opposes the induction of LTP through dephosphorylation of Y 1472 on the NR2B receptor subunit, leading to endocytosis of NR1/NR2B receptors (17, 18). Acute reduction in STEP expression by RNAi leads to increased surface expression and function of NR1/NR2B receptors (19), and STEP knockout (STEP −/− ) mice have enhanced hippocampal LTP (SI Appendix, Fig. S1). In addition, STEP 61 dephosphorylates a regulatory tyrosine within the activation loop of two enzymes critical for the development of synaptic strengthening, ERK1/2 and Fyn, thereby inactivating them (20,21). Together, these findings support the current model that STEP activity opposes the development of synaptic strengthening (22).Elevated levels of STEP 61 are found in several transgenic AD mouse models as well as human AD prefrontal cortex (Tg-2576 and J20) (23, 24). The increase in STEP 61 levels and activity contributes to the removal of NR1/NR2B complexes from synapses (24). Given that STEP 61 regulates Aβ-induced internalization of NR1/...