Abstract
Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.
Highlights
Disruption of the associative/dissociative balance in synaptic plasticity that is the basis of learning and memory begins in Mild Cognitive Impairment (MCI) and progresses as Alzheimer’s disease continues
While several cell surface proteins have been identified as receptors of accumulation of synaptotoxic beta amyloid (Abeta) oligomers [32], therapeutic ligands for these receptors have not been demonstrated to be effective in displacing bound Abeta oligomers
Neuronal cell lines can be used in high-throughput screens, but they do not replicate the electrophysiological state-dependent signaling of primary neuronal cultures and are unlikely to adequately model the subtle alterations in this signaling that are caused by oligomers during the earliest manifestations of the disease state [44]
Summary
Disruption of the associative/dissociative balance in synaptic plasticity that is the basis of learning and memory begins in Mild Cognitive Impairment (MCI) and progresses as Alzheimer’s disease continues. Evidence suggests this cognitive decline is caused by the accumulation of Abeta 1–42 oligomers in the brains of these patients [1,2,3,4,5,6] Oligomers disrupt this balance by binding to plasma membrane proteins [7,8,9,10,11,12,13,14,15], changing intracellular calcium levels [11,16,17,18], inducing tau mislocalization, disrupting microtubules [17,18], altering membrane trafficking processes and surface expression levels of critical synaptic ion channels [19,20,21] and causing reversible spine loss in neurons [17,22,23,24,25]. There is disagreement over the identity of the form of Abeta oligomer responsible for human cognitive loss, creating difficulty in extrapolating in vitro results to in vivo efficacy
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