Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

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.

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

“…The second category involves Aβ impairment of synaptic connections by indirectly affecting NMDAR activity (see SI Discussion for more details about the first two categories). Postsynaptic Sigma-2/PGRMC1 (progesterone receptor membrane component 1) has been reported to serve as a receptor for 50∼75 kDa Aβ 1-42 oligomers (43). We report here a third system involving presynaptic neurons.…”

Elements in support of the ‘non-identity’ of the PGRMC1 protein with the σ2 receptor

“…Since σ 2 receptors were identified as the PGRMC1 protein complex in 2011 (Xu et al, 2011), a number of papers, in which this identity appears to be taken for granted, came out (Mir et al, 2012(Mir et al, , 2013Izzo et al, 2014aIzzo et al, , 2014b. However, controversy is still on about the identity of these receptors.…”

Effect of phosphatidylserine on memory in patients and rats with Alzheimer’s disease

“…However, patients experience memory and analysis obstacles during middle and advanced periods, and the most severe suffers cannot look after themselves, which puts a tremendous burden on the patients, their families, and society. Therefore, AD has become a disease that seriously threats the lives and health of the elderly second only to cardiovascular and cerebrovascular diseases, and cancer (Ballard et al, 2011;Izzo et al, 2014). This aging problem has become increasingly prominent in our country at present, and the incidence of AD is increasing year by year.…”