Amyloid Beta Postsynaptic Signaling through AKAP-anchored Calcineurin A? overproduction from APP is believed to contribute to impaired synaptic plasticity and decreased cognitive function in Alzheimer?s disease (AD). Individuals with Down syndrome (DS; trisomy 21) have an extra copy of APP that predisposes them to early-onset AD. Thus, elucidating how A? inhibits plasticity is important for understanding cognitive impairments associated with the development of dementia in AD and DS and could identify novel drug targets, diagnostics, and therapies. Rodent model studies indicate that calcineurin (CaN) phosphatase signaling could contribute to altered LTP/LTD synaptic plasticity, dendritic spine loss, and learning and memory impairments in AD. A?-induced spine loss may be further linked to altered gene expression through CaN activation of the transcription factor NFAT. Here we propose to test the novel hypotheses that AKAP79/150-CaN anchoring is required for A? activation of CaN signaling that regulates the balance between LTP/LTD signaling and NFAT transcription associated with dendritic spine/synapse loss.
Amyloid Beta Postsynaptic Signaling through AKAP-anchored Calcineurin In Alzheimer?s disease (AD) overproduction of amyloid beta (A?) protein fragments from the amyloid precursor protein (APP) is thought to interfere with the normal signaling functions of brain synapses during aging to interfere with learning and memory and cause dementia. The gene that makes APP is present on human chromosome 21, thus individuals with the intellectual disability Down syndrome (DS; trisomy 21), who have an extra copy of chromosome 21 and the APP gene, have higher levels of APP and A? in the brain. Accordingly, adults with DS during aging develop early-onset AD pathology by age 40 and eventually dementia. Elucidating how A??interferes with synaptic function is an important first step for understanding the mechanisms underlying cognitive impairments associated with AD and could result in the identification of novel drug targets and therapies. However, very little research to date has shed any light on the mechanisms by which A? engages and interacts with specific synaptic signaling pathways to cause neuronal dysfunction. Here, with the use of an innovative genetically engineered mouse model, we will test the novel idea that A? activates signaling that impairs synaptic function through a protein called Calcineurin that is specifically anchored at synapses by a protein called AKAP150. Importantly, these studies will investigate whether targeted disruption of AKAP150-anchored Calcineurin signaling at synapses could be worth exploring as a viable therapy for preventing synaptic and cognitive dysfunction in AD.
| Freund, Ronald K; Gibson, Emily S; Potter, Huntington et al. (2016) Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid ?-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss. Mol Pharmacol 89:552-9 |
