Anne Andrews Group
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­SRIs to Delay 5-HT Degeneration in AD: Effects on BDNF and Neurogenesis

­ Widespread neurodegeneration occurs across multiple neurotransmitter systems in Alzheimer’s disease (AD), yet little research has focused on the specific consequences of the extensive degeneration that takes place in the serotonin transmitter system. Because of the key role that serotonin plays in regulating cognitive function and mood, it is likely that loss of serotonergic innervation to the forebrain contributes to progressive memory dysfunction, as well as to the symptoms of depression and anxiety that appear in the moderate to late stages of AD. Brain-derived neurotrophic factor (BDNF), a neurotrophin regulated by serotonin, is known to play a critical role in adult neuronal plasticity including hippocampal long-term potentiation (a form of cellular memory) and in the generation and survival of new neurons in the hippocampus (neurogenesis). Recently, we demonstrated that decreased serotonin levels are associated with elevated BDNF in the hippocampus in transgenic mice co-expressing mutant human forms of amyloid precursor protein and presenilin-1 (APPswe/PS1ΔE9 mice). These mice are characterized by the early accumulation of brain amyloid deposits, neuritic plaques and memory dysfunction. These findings suggest that serotonergic degeneration occurs in this animal model of AD and that increased BDNF may be a compensatory response to β-amyloid toxicity. In the current proposal, we will explore this hypothesis. Specifically, we will determine the time course of serotonergic degeneration in APP/PS1 mice by immunocytochemistry. Further, we will temporally relate these changes to the modulation of BDNF expression and hippocampal neurogenesis. The potential for early administration of the serotonin-selective reuptake inhibiting antidepressant (SRI) citalopram to augment neurogenesis and memory function in APP/PS1 transgenic mice will be specifically assessed. Chronic administration of SRIs has been shown to increase hippocampal BDNF and neurogenesis during the treatment of depression, and this has been linked the therapeutic mechanism of action. These studies will provide insight into the role of serotonergic degeneration and its regulation of BDNF and neurogenesis as it pertains to AD-associated neuropathology. Moreover, they will determine whether SRIs are neuroprotective and/or neuroregenerative therapies to prevent or reduce cognitive and affective dysfunction when administered to patients beginning in the early stages of AD.  


Recent Publications

  1. The neurotoxin 2'-NH2-MPTP degenerates serotonin axons and evokes increases in hippocampal BDNF. B. A. Luellen, M. E. Szapacs, C. K. Materese and A. M. Andrews, Neuropharmacology, 50:297-308 (2006)  (ABSTRACT or PDF).
  2. Radical-induced degradation of liposome-encapsulated microtubules as a model of axonal damage due to oxidative stress. A. E. Counterman, T. G. D'Onofrio, A. M. Andrews and P. S. Weiss, Proceedings of the National Academy of Sciences, USA, 103:5262-5266 (2006)  (ABSTRACT or PDF).
  3. Reduced BDNF is associated with a loss of serotonergic innervation in the hippocampus of aging mice. B. A. Luellen, L. E. Bianco, L. M. Schneider and A. M. Andrews, Genes, Brain and Behavior, (Dec 2006) (ABSTRACT or PDF).

Techniques Used

Behavioral Methods
Elevated Plus Maze
Free Choice Exploration
Lashley Maze
Immunocytochemistry
Quantitative RT-PCR



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