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Pre- and post-synaptic cortical cholinergic deficits are proportional to amyloid plaque presence and density at preclinical stages of Alzheimer’s disease

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Abstract

Amyloid imaging has identified cognitively normal older people with plaques as a group possibly at increased risk for developing Alzheimer’s disease-related dementia. It is important to begin to thoroughly characterize this group so that preventative therapies might be tested. Existing cholinotropic agents are a logical choice for preventative therapy as experimental evidence suggests that they are anti-amyloidogenic and clinical trials have shown that they delay progression of mild cognitive impairment to dementia. A detailed understanding of the status of the cortical cholinergic system in preclinical AD is still lacking, however. For more than 30 years, depletion of the cortical cholinergic system has been known to be one of the characteristic features of AD. Reports to date have suggested that some cholinergic markers are altered prior to cognitive impairment while others may show changes only at later stages of dementia. These studies have generally been limited by relatively small sample sizes, long postmortem intervals and insufficient definition of control and AD subjects by the defining histopathology. We, therefore, examined pre- and post-synaptic elements of the cortical cholinergic system in frontal and parietal cortex in 87 deceased subjects, including non-demented elderly with and without amyloid plaques as well as demented persons with neuropathologically confirmed AD. Choline acetyltransferase (ChAT) activity was used as a presynaptic marker while displacement of 3H-pirenzepine binding by oxotremorine-M in the presence and absence of GppNHp was used to assess postsynaptic M1 receptor coupling. The results indicate that cortical ChAT activity as well as M1 receptor coupling are both significantly decreased in non-demented elderly subjects with amyloid plaques and are more pronounced in subjects with AD and dementia. These findings confirm that cortical cholinergic dysfunction in AD begins at the preclinical stage of disease and suggest that cholinotropic agents currently used for AD treatment are a logical choice for preventative therapy.

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Acknowledgments

The Banner Sun Health Research Institute Brain Donation Program is supported by the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research.

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  1. Department of Pharmacology, Arizona College of Osteopathic Medicine, Midwestern University, 19555 N 59th Ave, Glendale, AZ, 85308, USA

    Pamela E. Potter & Paula K. Rauschkolb

  2. Banner Sun Health Research Institute, Sun City, AZ, USA

    Yoga Pandya, Lucia I. Sue, Marwan N. Sabbagh, Douglas G. Walker & Thomas G. Beach

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  1. Pamela E. Potter
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  2. Paula K. Rauschkolb
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  3. Yoga Pandya
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  4. Lucia I. Sue
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  6. Douglas G. Walker
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  7. Thomas G. Beach
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Correspondence to Pamela E. Potter.

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Potter, P.E., Rauschkolb, P.K., Pandya, Y. et al. Pre- and post-synaptic cortical cholinergic deficits are proportional to amyloid plaque presence and density at preclinical stages of Alzheimer’s disease. Acta Neuropathol 122, 49–60 (2011). https://doi.org/10.1007/s00401-011-0831-1

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  • DOI: https://doi.org/10.1007/s00401-011-0831-1

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