Chronic Nicotine Restores Normal A

1
Chronic Nicotine Restores Normal Aß Levels and
Prevents Short-term Memory and E-LTP Impairment
in Aß Rat Model of Alzheimers Disease

• Marisa Srivareerat, Trinh T. Tran, Samina Salim,
  Abdulaziz M. Aleisa, Karim A. Alkadhi
• University of Houston, College of Pharmacy
• King Saud University, College of Pharmacy
• Neurobiology of Aging 32 (2011) 834-844

Kimberly Dunbar, PA-S2 January 2012
2
Overview

• Alzheimers disease is a progressive
  neurodegenerative disorder characterized by
  accumulation of ß-amyloid peptide, progressive
  cholinergic dysfunction, neurofibrillary tangles,
  and apoptosis in areas of the brain responsible
  for learning and memory

3
Overview

• Excess accumulation of Aß peptide impairs
  nicotinic acetylcholine receptor (nAChR) function
  by a mechanism thought to involve a7- and
  a4ß2-nAChR blockade

4
Terms

• BACE1 beta-site amyloid precursor protein
  cleaving enzyme 1
• Enzyme that cleaves amyloid precursor protein to
  make Aß
• BDNF brain-derived neurotropic factor
• Protein that acts on certain neurons in the CNS
  and PNS to support survival of existing neurons
  and encourage growth of new neurons and synapses

5
Objective

• To evaluate the effects of nicotine on Aß induced
  cognitive impairments of learning and short-term
  memory using various experimental approaches

6
Design

• Rats were continuously infused with Aß peptides
  while the control groups were infused with
  inactive reverse peptide for 2 weeks
• 4 groups
• Nicotine
• Nicotine/Aß
• Control
• Aß
• Nicotine groups were treated with nicotine
  infusions twice daily for 6 weeks, prior to and
  during Aß infusion
• Control groups received similar injections of
  normal saline

7
Inclusion Criteria

• Adult male Wistar rats
• Aged 49-52 days
• 200-225 g at beginning of the experiment

8
Evaluation

• RAWM radial arm water maze
• In vivo electrophysiological recordings of
  early-phase long-term potentiation
• Immunoblot assay to measure levels of BACE1,
  nAChR, and BDNF

9
Behavioral Results

• Nicotine/Aß rats required significantly fewer
  days to meet criterion (6.360.43) than the
  compared to Aß rats (7.730.69) in the learning
  phase
• Chronic nicotine treatment prevented an increase
  in short-term memory DTC in nicotine/Aß rats
  (5.640.41) compared to Aß rats (9.270.97)
• Nicotine did not have any statistical
  significance in normal rats

10
Electrophysiological Results
Control Nicotine Aß Nicotine/Aß
fEPSP slope (mV/ms) 1.380.07 1.330.10 0.930.11 1.450.08
5 min post-HFS ( of baseline) 162.785.0 180.407.28 133.485.50 160.789.39
1 hr post-HFS ( of baseline) 161.484.62 163.096.35 Significantly different 150.655.25
11
Immunoblot Results
Immunoreactivity Control Nicotine Aß Nicotine/Aß
BACE1 (ratio to control) - 1.110.07 1.550.10 1.180.11
Aß1-40 (ratio to control) - 0.990.05 1.530.06 1.150.09
BDNF (ratio to control) - ?53 ?19 ?31
Immunoreactivity (ratio to control) a7-nAChR a4-nAChR ß2-nAChR
Aß ?39 ?31 ?16
Nicotine/Aß ?72 ?68 ?42
12
Conclusions

• Cell protection against Aß toxicity can be
  achieved with chronic nicotine treatment by
  upregulation of nAChRs, activation of nAChRs to
  mediate nicotine protection against Ca2
  -dependent excitotoxicity, and inhibition of
  ß-amyloidosis, possibly due to upregulation of
  BDNF.
• A protective effect against Aß-enhanced
  neurotoxicty can be achieved with nicotinic
  receptor stimulation and may prevent cognitive
  impairment associated with Alzheimers disease.

13
Comments

• Misrepresented population only used male rats
• Sample size was never mentioned
• No value given for 1hr post-HFS for Aß
• SEM (standard error of the mean) used instead of
  SD (standard deviation)

14
Level of Evidence
15
References

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• Srivareerat M, Tran T, Salim S, et al. Chronic
  nicotine restores normal Aß levels and prevents
  short-term memory and E-LTP impairment in Aß rat
  model of Alzheimers disease. Neurobiology of
  Aging. 2011 32 834-844.
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