ABSTRACT
The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAß) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAß and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oAß, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oAß and oTau requires expression of APP. Finally, the toxic effect of both extracellular oAß and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oAß- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of Aß and/or Tau.
Subject(s)
Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Long-Term Potentiation , Memory Disorders/physiopathology , Neurons/physiology , Peptide Fragments/metabolism , Protein Multimerization , tau Proteins/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/toxicity , Animals , Cells, Cultured , Disease Models, Animal , Humans , Mice, Inbred C57BL , Mice, Knockout , Peptide Fragments/toxicity , Protein Binding , tau Proteins/toxicityABSTRACT
Learning and memory and the underlying cellular correlate, long-term synaptic plasticity, involve regulation by posttranslational modifications (PTMs). Here we demonstrate that conjugation with the small ubiquitin-like modifier (SUMO) is a novel PTM required for normal synaptic and cognitive functioning. Acute inhibition of SUMOylation impairs long-term potentiation (LTP) and hippocampal-dependent learning. Since Alzheimer's disease (AD) prominently features both synaptic and PTM dysregulation, we investigated SUMOylation under pathology induced by amyloid-ß (Aß), a primary neurotoxic molecule implicated in AD. We observed that SUMOylation is dysregulated in both human AD brain tissue and the Tg2576 transgenic AD mouse model. While neuronal activation normally induced upregulation of SUMOylation, this effect was impaired by Aß42 oligomers. However, supplementing SUMOylation via transduction of its conjugating enzyme, Ubc9, rescued Aß-induced deficits in LTP and hippocampal-dependent learning and memory. Our data establish SUMO as a novel regulator of LTP and hippocampal-dependent cognition and additionally implicate SUMOylation impairments in AD pathogenesis.
Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Cognition/physiology , Neuronal Plasticity/physiology , SUMO-1 Protein/metabolism , Aged , Aged, 80 and over , Amyloid beta-Peptides/metabolism , Animals , Disease Models, Animal , Hippocampus/metabolism , Hippocampus/physiology , Hippocampus/physiopathology , Humans , Long-Term Potentiation/physiology , Male , Memory/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Sumoylation/physiologyABSTRACT
Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.
