Mirra, Suzanne S

Publication Detail

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Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses.

Claudia G Almeida; Davide Tampellini; Reisuke H Takahashi; Paul Greengard; Michael T Lin; Eric M Snyder; Gunnar K Gouras (Profiled Author: Greengard, Paul)

Department of Neurology and Neuroscience, Laboratory of Alzheimer's Disease Neurobiology, Weill Medical College of Cornell University, 525 E 68th Street, NY 10021, USA.
Neurobiology of disease 2005;20(2):187-98.

Synaptic dysfunction is increasingly viewed as an early manifestation of Alzheimer's disease (AD), but the cellular mechanism by which beta-amyloid (Abeta) may affect synapses remains unclear. Since cultured neurons derived from APP mutant transgenic mice secrete elevated levels of Abeta and parallel the subcellular Abeta accumulation seen in vivo, we asked whether alterations in synapses occur in this setting. We report that cultured Tg2576 APP mutant neurons have selective alterations in pre- and post-synaptic compartments compared to wild-type neurons. Post-synaptic compartments appear fewer in number and smaller, while active pre-synaptic compartments appear fewer in number and enlarged. Among the earliest changes in synaptic composition in APP mutant neurons were reductions in PSD-95, a protein involved in recruiting and anchoring glutamate receptor subunits to the post-synaptic density. In agreement, we observed early reductions in surface expression of glutamate receptor subunit GluR1 in APP mutant neurons. We provide evidence that Abeta is specifically involved in these alterations in synaptic biology, since alterations in PSD-95 and GluR1 are blocked by gamma-secretase inhibition, and since exogenous addition of synthetic Abeta to wild-type neurons parallels changes in synaptic PSD-95 and GluR1 observed in APP mutant neurons.

1 Originating Grant

• 1.

  GREENGARD, PAUL

  Signaling Transduction and Alzheimer's Disease

  30 September 1997 - 31 January 2012

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 23,889,772

Scientific Context

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