Carlos Sindreu

Mentor: Dan Storm
Box: 357750
Phone: 206-543-9280
Email: bsindreu@u.washington.edu
http://depts.washington.edu/phcol/faculty/storm.php

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Aging is commonly accompanied by memory impairment, and in more serious conditions, dementia or Alzheimer's disease (AD). The Erk1/2 MAP kinase signaling pathway is now recognized as one of the major pathways necessary for long-term memory formation. Decreases in Erk1/2 activity associated with aging have been described, but the factors initiating them are unknown. In addition, Erk1/2 has been implicated in tau, presenilin, and neurofilament phosphorylation, all of which may be important in AD.

Extracellular zinc regulates synaptic transmission and plasticity in cortical areas of the brain, and excess zinc levels are a prominent feature of AD. Furthermore, zinc can trigger the accumulation of the amyloid beta-peptide in vitro, and genetic ablation of the synaptic zinc transporter ZnT3 in mice markedly attenuates amyloid burden. On the other hand, increased excitotoxicity and reduced ZnT3 levels have been observed in mice with accelerated brain senescence (SAMP10 mice).

Calos Sindreu's research seeks to understand the impact of brain zinc on Erk1/2 activation. Given that oxidative stress is a hallmark of the aging brain, and that even mild endogenous oxidants can release zinc from intracellular metallothioneins, altered zinc homeostasis may result in deficits in neuroplasticity and cognition in part via dysregulation of the Erk/MAPK pathway.

Publications
Kokaia M, Asztely F, Olofsdotter K, Sindreu CB, Kullmann DM, Lindvall O. Endogenous neurotrophin-3 regulates short-term plasticity at lateral perforant path-granule cell synapses. J. Neurosci. 1998; 18 (21): 8730-9.

Sindreu CB, Varoqui H, Erickson JD, Perez-Clausell J. Boutons containing vesicular zinc define a subpopulation of synapses with low AMPAR content in rat hippocampus. Cereb Cortex. 2003; 13 (8): 823-9.

Wang Z, Sindreu CB, Li V, Nudelman A, Chan GC, Storm DR. Pheromone detection in male mice depends on signaling through the type 3 adenylyl cyclase in the main olfactory epithelium. J. Neurosci. 2006; 26 (28): 7375-9.

Sindreu CB, Scheiner ZS, Storm DR. Ca2+ -stimulated adenylyl cyclases regulate ERK-dependent activation of MSK1 during fear conditioning. Neuron. 2007; 53 (1): 79-89.

Sindreu CB, Storm DR. How I learned to stop worrying and love calcineurin. Nat Neurosci. 2008; 11 (5): 527-528.