Inhaled anesthetics increase the aggregation of amyloid beta in vitro through the stabilization of intermediate oligomers, a species thought to cause neurocognitive dysfunction in Alzheimer's disease (AD). Others have reported that production of amyloid beta is also increased. Thus, inhaled anesthetics may contribute to diminished cognition by increasing the brain concentration of amyloid beta in a toxic form. We have found that anesthetics enhanced plaque load in Tg2576 transgenic mice (a model of AD), but produced no incremental cognitive deficit. We suspect this is due to either a floor effect or insufficient time for the new neuropathology to produce cognitive decline. We now propose to expand these studies in a more recent animal model with 3 transgenes, involving several molecular steps in AD pathogenesis. We will determine the interaction between anesthetics and AD by exposing these animals to five different anesthetics at various ages to address the hypothesis that the anesthetic enhances the rate of amyloid and tau histopathology and cognitive decline, and that a specific window of vulnerability exists. In addition, the levels of the small amyloid beta oligomers, hyperphosphorylated tau, caspase-3 and synaptic markers will be biochemically quantitated after anesthetic exposures in order to test our mechanistic hypothesis. We will also initiate limited interventional trials. Because of the huge number of patients that receive anesthetics, and the public health and societal challenge of caring for the demented, it is imperative that we design our perioperative care in a way that avoids contributions to neurodegeneration.

Public Health Relevance

Anesthetics have effects on the brain that outlast the period of anesthesia itself. The ability of volatile anesthetics to make proteins clump together (aggregation), produce pathology and learning and memory dysfunction resembling AD in mice, suggests the need for more rigorous evaluation of this issue, particularly in the elderly, as well as the need to investigate the safest anesthetic compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031742-05
Application #
8286955
Study Section
Special Emphasis Panel (ZRG1-CND-E (90))
Program Officer
Refolo, Lorenzo
Project Start
2008-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$306,120
Indirect Cost
$111,758
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tang, Junxia X; Mardini, Feras; Janik, Luke S et al. (2013) Modulation of murine Alzheimer pathogenesis and behavior by surgery. Ann Surg 257:439-48
Cheng, Ying; Thomas, Adia; Mardini, Feras et al. (2012) Neurodevelopmental consequences of sub-clinical carbon monoxide exposure in newborn mice. PLoS One 7:e32029
Tang, Junxia X; Mardini, Feras; Caltagarone, Breanna M et al. (2011) Anesthesia in presymptomatic Alzheimer's disease: a study using the triple-transgenic mouse model. Alzheimers Dement 7:521-531.e1
Tang, Junxia X; Eckenhoff, Maryellen F; Eckenhoff, Roderic G (2011) Anesthetic modulation of neuroinflammation in Alzheimer's disease. Curr Opin Anaesthesiol 24:389-94
Tang, Junxia; Eckenhoff, Maryellen F; Eckenhoff, Roderic G (2010) Anesthesia and the old brain. Anesth Analg 110:421-6
Bianchi, Shannon L; Caltagarone, Breanna M; Laferla, Frank M et al. (2010) Inhaled anesthetic potency in aged Alzheimer mice. Anesth Analg 110:427-30