Activation of D1/D5 Dopamine Receptors Protects Neurons from Synapse Dysfunction Induced by Amyloid-β Oligomers

Abstract

Soluble oligomers of the amyloid-␤ peptide (A␤Os) accumulate in the brains of Alzheimer disease (AD) patients and are implicated in synapse failure and early memory loss in AD. A␤Os have been shown to impact synapse function by inhibiting long term potentiation, facilitating the induction of long term depression and inducing internalization of both AMPA and NMDA glutamate receptors, critical players in plasticity mechanisms. Because activation of dopamine D1/D5 receptors plays important roles in memory circuits by increasing the insertion of AMPA and NMDA receptors at synapses, we hypothesized that selective activation of D1/D5 receptors could protect synapses from the deleterious action of A␤Os. We show that SKF81297, a selective D1/D5 receptor agonist, prevented the reduction in surface levels of AMPA and NMDA receptors induced by A␤Os in hippocampal neurons in culture. Protection by SKF81297 was abrogated by the specific D1/D5 antagonist, SCH23390. Levels of AMPA receptor subunit GluR1 phosphorylated at Ser 845 , which regulates AMPA receptor association with the plasma membrane, were reduced in a calcineurin-dependent manner in the presence of A␤Os, and treatment with SKF81297 prevented this reduction. Establishing the functional relevance of these findings, SKF81297 blocked the impairment of long term potentiation induced by A␤Os in hippocampal slices. Results suggest that D1/D5 receptors may be relevant targets for development of novel pharmacological approaches to prevent synapse failure in AD. Alzheimer disease (AD)2 is the main cause of dementia among the elderly, and current estimates indicate that it affects around 25 million people worldwide (1, 2). Although much is known about the pathophysiology of AD, there is still no cure or effective treatment capable of slowing the progression of the disease. For this reason, development of novel pharmacological strategies for treatment is of critical importance.Considerable evidence indicates that soluble oligomers of the amyloid-␤ peptide (A␤Os) accumulate in the brains of AD patients and are responsible for synapse dysfunction and memory loss in AD (3-5). Among other deleterious actions, A␤Os impair synaptic plasticity, likely leading to memory loss at early stages of the disease. A␤Os have been shown to inhibit long term potentiation (LTP) (4, 6, 7), facilitate the induction of long term depression (LTD) (8, 9), induce internalization of , and increase activation of protein phosphatases, such as calcineurin and protein phosphatase-1 (9, 10, 15, 16), finally leading to spine loss (14).Dopamine receptors have been grouped into two families: D1-type and D2-type (17). The D1 family comprises D1 and D5 receptor subtypes, which are mostly coupled to G␣ s and stimulate production of the second messenger cyclic AMP, leading to activation of protein kinase A (PKA) (17). D1/D5 receptors play important roles in cognition, mediating plasticity and specific aspects of cognitive function, including working and spatial learning and memory processes (18). Stimulation of D...

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“…Besides IRs, other proteins important for synaptic plasticity, including NMDA- (47,48) and AMPA-type glutamate receptors (49), are removed from the cell surface when neurons are exposed to oligomers, indicating a broad impact on synapses. Oligomer actions are thought to underlie other aspects of brain dysfunction in AD, activating signaling pathways that lead to abnormal tau phosphorylation (50)(51)(52) and oxidative stress (53)(54)(55), both hallmarks of AD pathology.…”