Anti-PrP antibody rescues cognition and synapses in transgenic alzheimer mice.

Objective: Amyloid-beta oligomers (Aßo) trigger the development of Alzheimer's disease (AD) pathophysiology. Cellular prion protein (PrPC) initiates synaptic damage as a high affinity receptor for Aßo. Here, we evaluated the preclinical therapeutic efficacy of a fully human monoclonal antibody against PrPC.

Rescue of Transgenic Alzheimer's Pathophysiology by Polymeric Cellular Prion Protein Antagonists.

Cellular prion protein (PrP) binds the scrapie conformation of PrP (PrP) and oligomeric β-amyloid peptide (Aβo) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer's disease (AD), respectively. We conducted cellular and biochemical screens for compounds blocking PrP interaction with Aβo. A polymeric degradant of an antibiotic targets Aβo binding sites on PrP with low nanomolar affinity and prevents Aβo-induced pathophysiology.

Liquid and Hydrogel Phases of PrP Linked to Conformation Shifts and Triggered by Alzheimer's Amyloid-β Oligomers.

Protein phase separation by low-complexity, intrinsically disordered domains generates membraneless organelles and links to neurodegeneration. Cellular prion protein (PrP) contains such domains, causes spongiform degeneration, and is a receptor for Alzheimer's amyloid-β oligomers (Aβo). Here, we show that PrP separates as a liquid phase, in which α-helical Thr become unfolded.

Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models.

Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain.

Fyn inhibition rescues established memory and synapse loss in Alzheimer mice.

Objective: Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression.

Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein.

Soluble amyloid-β oligomers (Aβo) trigger Alzheimer's disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrP(C)). At the postsynaptic density (PSD), extracellular Aβo bound to lipid-anchored PrP(C) activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo-PrP(C) with Fyn.

Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons.

Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP(C)) selectively binds oligomeric Aβ and can mediate Alzheimer's disease-related phenotypes. We examined the specificity, distribution and signaling of Aβ-PrP(C) complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons.

Memory impairment in transgenic Alzheimer mice requires cellular prion protein.

Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function.

Beta-amyloid oligomers and cellular prion protein in Alzheimer's disease.

Prefibrillar oligomers of the beta-amyloid peptide (A beta) are recognized as potential mediators of Alzheimer's disease (AD) pathophysiology. Deficits in synaptic function, neurotoxicity, and the progression of AD have all been linked to the oligomeric A beta assemblies rather than to A beta monomers or to amyloid plaques. However, the molecular sites of A beta oligomer action have remained largely unknown.

Prediction of clinical drug efficacy by classification of drug-induced genomic expression profiles in vitro.

Assays of drug action typically evaluate biochemical activity. However, accurately matching therapeutic efficacy with biochemical activity is a challenge. High-content cellular assays seek to bridge this gap by capturing broad information about the cellular physiology of drug action.