Chronic Nicotine Restores Normal Aβ Levels and Prevents Short-term Memory and E-LTP Impairment in Aβ Rat Model of Alzheimer’s Disease Marisa Srivareerat, Trinh T. Tran, Samina Salim, Abdulaziz M. Aleisa, Karim A. Alkadhi

University of Houston, College of PharmacyKing Saud University, College of Pharmacy

Neurobiology of Aging 32 (2011) 834-844

Kimberly Dunbar, PA-S2January 2012

Overview

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

Overview

•Excess accumulation of Aβ peptide impairs nicotinic acetylcholine receptor (nAChR) function by a mechanism thought to involve α7- and α4β2-nAChR blockade

Terms

•BACE1: beta-site amyloid precursor protein cleaving enzyme 1▫Enzyme that cleaves amyloid precursor

protein to make Aβ•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

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

Objective

Design• Rats were continuously infused with Aβ peptides

while the control groups were infused with inactive reverse peptide for 2 weeks

• 4 groups▫ Nicotine▫ Nicotine/Aβ▫ Control▫ Aβ

• Nicotine groups were treated with nicotine infusions twice daily for 6 weeks, prior to and during Aβ infusion

• Control groups received similar injections of normal saline

Inclusion Criteria

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

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

Behavioral Results•Nicotine/Aβ rats required significantly

fewer days to meet criterion (6.36±0.43) than the compared to Aβ rats (7.73±0.69) in the learning phase

•Chronic nicotine treatment prevented an increase in short-term memory DTC in nicotine/Aβ rats (5.64±0.41) compared to Aβ rats (9.27±0.97)

•Nicotine did not have any statistical significance in normal rats

Electrophysiological ResultsControl Nicotine Aβ Nicotine/

Aβ

fEPSP slope(mV/ms)

1.38±0.07 1.33±0.10 0.93±0.11 1.45±0.08

5 min post-HFS(% of

baseline)

162.78±5.0 180.40±7.28

133.48±5.50

160.78±9.39

1 hr post-HFS(% of

baseline)

161.48±4.62

163.09±6.35

“Significantly different”

150.65±5.25

Immunoblot ResultsImmunoreactivity

Control Nicotine Aβ Nicotine/Aβ

BACE1(ratio to control)

- 1.11±0.07 1.55±0.10 1.18±0.11

Aβ1-40(ratio to control)

- 0.99±0.05 1.53±0.06 1.15±0.09

BDNF(ratio to control)

- ↑53% ↑19% ↑31%

Immunoreactivity(ratio to control)

α7-nAChR α4-nAChR β2-nAChR

Aβ ↓39% ↓31% ↓16%

Nicotine/Aβ ↑72% ↑68% ↑42%

Conclusions• Cell protection against Aβ 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 β-amyloidosis, possibly due to upregulation of BDNF.

• A protective effect against Aβ-enhanced neurotoxicty can be achieved with nicotinic receptor stimulation and may prevent cognitive impairment associated with Alzheimer’s disease.

Comments

•Misrepresented population – only used male rats

•Sample size was never mentioned•No value given for 1hr post-HFS for Aβ•SEM (standard error of the mean) used

instead of SD (standard deviation)

Level of Evidence

References• De Fer, Thomas M., Brisco, Meredith A., Mullur, Rashmi S. The Washington

Manual of Outpatient Internal Medicine. Philadelphia, PA: Lippincott Williams & Wilkins; 2010.

• Nagele, P. Misuse of standard error of the mean when reporting variability of a sample: A critical evaluation of four anaesthesia journals. British Journal of Anaesthesia. 2003;90(4): 514-516. doi: 10.1093/bja/aeg087.

• Srivareerat M, Tran T, Salim S, et al. Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer’s disease. Neurobiology of Aging. 2011; 32: 834-844.

• Wikipedia contributors. Beta-secretase 1. Wikipedia, The Free Encyclopedia. June 22, 2011, 21:47 UTC. Available at: http://en.wikipedia.org/w/index.php?title=Beta-secretase_1&oldid=435709526. Accessed January 23, 2012.

• Wikipedia contributors. Brain-derived neurotrophic factor. Wikipedia, The Free Encyclopedia. January 16, 2012, 22:48 UTC. Available at:http://en.wikipedia.org/w/index.php?title=Brain-derived_neurotrophic_factor&oldid=471764562. Accessed January 23, 2012.