Cortical Α7 Nicotinic Acetylcholine Receptor and Β-Amyloid Levels In

ORIGINAL CONTRIBUTION Cortical ␣7 Nicotinic Acetylcholine Receptor and ␤-Amyloid Levels in Early Alzheimer Disease

Milos D. Ikonomovic, MD; Lynn Wecker, PhD; Eric E. Abrahamson, PhD; Joanne Wuu, ScM; Scott E. Counts, PhD; Stephen D. Ginsberg, PhD; Elliott J. Mufson, PhD; Steven T. DeKosky, MD

Objective: To examine ␣7 nicotinic acetylcholine re- moderate AD (P=.02), lower Mini-Mental State Exami- ceptor (nAChR) binding and ␤-amyloid (A␤) peptide load nation scores (P=.003), presence of cortical A␤ plaques in superior frontal cortex (SFC) across clinical and neu- (P =.02), and likelihood of AD diagnosis by the ropathological stages of Alzheimer disease (AD). National Institute on Aging–Reagan criteria (P=.002). Increased ␣7 nAChR binding was associated with ␣ Design: Quantitative measures of 7 nAChR by National Institute on Aging–Reagan diagnosis (P=.02) 3 ␤ [ H]methyllycaconitine binding and A concentration by and, albeit weakly, the presence of cortical A␤ plaques enzyme-linked immunosorbent assay in SFC were com- (P=.08). There was no correlation between the 2 bio- pared across subjects with antemortem clinical classifi- chemical measures. cation of no cognitive impairment, mild cognitive impairment, or mild to moderate AD, and with postmortem Conclusions: These observations suggest that during the neuropathological diagnoses. clinical progression from normal cognition to neurodegenerative disease state, total A␤ peptide concentration Setting: Academic medical center. increases while ␣7 nAChRs remain relatively stable in Subjects: Twenty-nine elderly retired clergy. SFC. Regardless of subjects’ clinical status, however, elevated ␣7 nAChR binding is associated with increased ␤ Main Outcome Measures: Quantitative measures of A plaque pathology, supporting the hypothesis that cel- ␣7 nAChR binding and A␤ peptide concentration in SFC. lular expression of these receptors may be upregulated selectively in A␤ plaque–burdened brain areas. Results: Higher concentrations of total A␤ peptide in SFC were associated with clinical diagnosis of mild to Arch Neurol. 2009;66(5):646-651

HOLINERGIC SYNAPTIC DYS- quantified ␣7 nAChR binding and total A␤ Author Affiliations: function contributes to peptide concentration in superior frontal Departments of Neurology cognitive impairment in cortex (SFC) from subjects who partici- (Drs Ikonomovic, Abrahamson, Alzheimer disease (AD). pated in the Religious Orders Study.20,21 and DeKosky) and Psychiatry These changes may be The status of these 2 biochemical mea- (Drs Ikonomovic and due, in part, to increased concentrations sures was examined across subjects’ groups DeKosky), University of C ␤ ␤ 1 defined by clinical diagnoses of no cogni- Pittsburgh School of Medicine, of -amyloid (A ) peptides and their in- teractions with nicotinic acetylcholine re- tive impairment (NCI), mild cognitive im- Pittsburgh, Pennsylvania; pairment (MCI), and early AD stage (mild Department of Psychiatry and ceptors (nAChRs), which are essential for Behavioral Medicine, University normal cognitive function.2,3 ␤-amyloid to moderate AD [mAD]), or neuropatho- of South Florida College of binds to nAChRs, particularly the ␣7 sub- logical diagnosis. Medicine, Tampa (Dr Wecker); class4,5; this may alter receptor func- Neurostatistics Section, tion6-10 and also result in A␤ internaliza- METHODS Department of Neurology, Emory University, Atlanta, tion, fibrillization, and deposition into 4,11-13 Georgia (Ms Wuu); Department plaques and cerebral vasculature. The SUBJECTS of Neurological Sciences, Rush status of ␣7 nAChRs in AD is controver- University Medical Center, sial as there are reports of increases, de- This study included 29 participants in the Re- Chicago, Illinois (Drs Counts creases, or stability in AD.14-18 While ligious Orders Study, a longitudinal clinical- and Mufson); and Nathan Kline non-␣7 nAChR binding in frontal cortex pathological study of aging and AD in retired Institute and Departments of Catholic nuns, priests, and brothers.20 Inclu- declines early in AD,19 quantitative bio- Psychiatry, Physiology, and ␣ sion criteria and a description of the clinical Neuroscience, New York chemical studies specific for 7 nAChRs evaluation have been published.20,21 At the last University School of Medicine, in subjects with preclinical and early AD clinical evaluation (Ͻ12 months prior to death), Orangeburg (Dr Ginsberg). remain to be performed. The current study subjects were classified as having NCI, MCI,

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 1. Demographic, Clinical, and Neuropathological Characteristics by Diagnostic Group

Clinical Diagnosis CERAD Diagnosis

NCI MCI mAD Not AD AD Variable (n=12) (n=9) (n=8) P Value (n=10) (n=19)a P Value Age, y, mean (SD) 86.1 (5.5) 85.3 (3.6) 89.4 (5.0) .13b 85.0 (4.5) 87.7 (5.0) .19b Male, No. (%) 4 (33) 3 (33) 3 (38) Ͼ.99c 4 (40) 6 (32) .70c Education, y, mean (SD) 18.5 (2.7) 18.9 (2.5) 15.9 (3.3) .11b 17.8 (3.0) 17.9 (3.1) .85b APOE ε4, No. (%) 0 0 2 (25) .07c 0 2 (11) Ͼ.99c MMSE score, mean (SD) 28.7 (1.1)d 27.1 (2.5) 12.8 (5.8) Ͻ.001b 27.7 (2.5) 21.4 (8.8)d .06b PMI, h, mean (SD) 5.3 (3.3) 5.0 (3.6) 4.4 (2.1) .78b 5.8 (3.9) 4.5 (2.5) .60b Braak stage, No. I-II 1 3 1 4 1 III-IV 10 6 2 .04b 6 12 .004b V10506 NIA-Reagan diagnosis, No. LL 5 5 0 10 0 IL 7 4 5 .02b 016Ͻ.001b HL 0 0 3 0 3 CERAD diagnosis, No. Not AD 5 5 0 .04c ADa 748

Abbreviations: AD, Alzheimer disease; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; HL, high likelihood of AD; IL, intermediate likelihood of AD; LL, low likelihood of AD; mAD, mild to moderate AD; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; NCI, no cognitive impairment; NIA, National Institute on Aging; PMI, postmortem interval. a Includes CERAD diagnosis of possible, probable, and definite AD. b Wilcoxon rank sum test or Kruskal-Wallis test. c Fisher exact test. d Mini-Mental State Examination score not available for 1 case.

or mAD (Table 1). Diagnosis of AD dementia was made using Tocris Cookson Ltd, Bristol, England) in Tris-HCl buffer con- standard criteria.22 Mild cognitive impairment was defined as taining 0.1% bovine serum albumin. Nonspecific binding was impairment on neuropsychological testing but without a diag- measured in the presence of 1mM nicotine. After a 2-hour in- nosis of dementia by the examining neurologist,20 criteria simi- cubation on ice, bound ligand was separated from free ligand lar to those describing patients who were not cognitively in- using Whatman GF/B filters (Whatman, Florham Park, New tact but nonetheless did not meet the criteria for dementia.23-26 Jersey), presoaked in 0.3% polyethyleneimine. Filters were rinsed A consensus conference of neurologists and neuropsycholo- with Tris-HCl buffer, placed in scintillation vials, and shaken gists reviewed all the clinical and neuroimaging data, medical in scintillation fluid for 1 hour before radioactivity was deter- records, and interviews with family members and assigned a mined. Specific binding was calculated as the difference be- final diagnosis. tween total and nonspecific binding. Results were expressed as femtomoles per milligram of protein. NEUROPATHOLOGICAL EVALUATION A␤ ELISA ASSAY Neuropathological diagnosis of AD (possible, probable, or definite AD) or not AD (Table 1) was based on modified criteria The A␤ assay was performed using a previously reported pro- by the Consortium to Establish a Registry for Alzheimer’s Dis- tocol.33 Frozen SFC samples were homogenized (150 mg of tis- ease (CERAD),27 which applied semiquantitative estimates of sue wet weight/mL of phosphate-buffered saline, pH=7.4) and neuritic plaque density by a board-certified neuropathologist 30 mg of homogenized tissue were sonicated in 70% formic acid blinded to the clinical diagnosis.28 Subjects were also assigned and centrifuged at 109 000ϫg at 4°C for 1 hour, resulting in a National Institute on Aging (NIA)–Reagan neuropathologi- samples containing both soluble and formic acid–extracted in- cal diagnosis29 and a Braak score based on the presence of neu- soluble A␤ peptides. The supernatant was neutralized with 1M rofibrillary tangles.30 Subjects with pathology other than AD Tris and 0.5M sodium phosphate, and the samples were as- were excluded from the study. sayed using a fluorescent-based ELISA (BioSource, Carlsbad, California) following the kit’s instructions, with a capture an- [3H]METHYLLYCACONITINE BINDING ASSAY tibody specific for the amino terminus of A␤ (amino acids 1-16) ␤ ␤ and detection antibodies specific for A 40 and A 42 peptides. Fresh frozen SFC (Brodmann area 9) gray matter was divided Values were determined from standard curves using synthetic ␤ ␤ into aliquots for nAChR binding and A␤ peptide enzyme- A 1-40 and A 1-42 peptides (BioSource) and expressed as pico- ␤ linked immunosorbent assay (ELISA). For ␣7 nAChR bind- moles per gram of wet brain tissue. “Total” A values repre- ␤ ␤ ing, samples were homogenized in 10 volumes of 50mM Tris- sent a sum of A 1-40 and A 1-42 peptide values. hydrochloride (Tris-HCl) buffer (pH=7.0), centrifuged twice at 40 000ϫg for 10 minutes, resuspended in Tris buffer, and STATISTICAL ANALYSIS stored at −80°C. Samples were thawed and resuspended in an equal volume of Tris buffer containing 0.1% bovine serum al- ␤-amyloid levels were log-transformed because of data skew- bumin.31,32 Samples, 0.5 mg of protein each, were combined with ness. Comparisons of demographic characteristics, MLA bind- 9.5nM [3H]methyllycaconitine (MLA) (159.1ϫ1010 Bq/mmol; ing, and A␤ levels between clinically or neuropathologically de-

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CERAD Diagnosis, Mean Clinical Diagnosis, Mean (SD) (SD)

Variable NCI MCI mADP Valuea Not AD ADb P Valuea MLA 2.4 (1.0) 2.4 (1.5) 3.0 (1.4) .68 1.8 (0.7) 2.9 (1.3) .08 (n=12) (n=7) (n=5) (n=8) (n=16) c A␤40 2.3 (1.6) 2.5 (2.2) 4.3 (1.7) .13 1.7 (1.9) 4.0 (1.6) .06 (n=5) (n=8) (n=7) (n=8) (n=12) c A␤42 5.0 (2.5) 5.2 (2.4) 7.3 (0.3) .02 4.1 (2.5) 7.1 (0.4) .02 (n=5) (n=8) (n=7) (n=8) (n=12) Total A␤c 5.1 (2.5) 5.3 (2.4) 7.5 (0.4) .02 4.2 (2.4) 7.3 (0.5) .02 (n=5) (n=8) (n=7) (n=8) (n=12)

Abbreviations: A␤, ␤-amyloid; AD, Alzheimer disease; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; ELISA, enzyme-linked immunosorbent assay; mAD, mild to moderate AD; MCI, mild cognitive impairment; MLA, [3H]methyllycaconitine; NCI, no cognitive impairment; a Wilcoxon rank sum test or Kruskal-Wallis test. b Includes CERAD diagnosis of possible, probable, and definite AD. c The A␤ levels were log-transformed.

fined groups were performed using the Wilcoxon rank sum test, MLA BINDING AND A␤ CONCENTRATION: Kruskal-Wallis test, or the Fisher exact test, as appropriate. The ASSOCIATION WITH association between demographic characteristics and MLA bind- CLINICAL-NEUROPATHOLOGICAL FACTORS ing or A␤ levels was assessed by Spearman rank correlation or Wilcoxon rank sum test. Partial correlation was used for additional analyses adjusting for age. The correlation between MLA There was no association of MLA binding with any of the binding and A␤ levels was assessed by Spearman correlation. demographic or clinical variables examined. Higher MLA The level of statistical significance was set at .05 (2-sided). binding levels correlated with greater likelihood of AD by the NIA-Reagan diagnosis (r=−0.47; P=.02) (Table 3) and weakly with Braak staging. There was an associa- RESULTS tion of higher A␤ concentrations with more advanced age (r=0.48-0.56; P=.01-.03; Table 3), but not with sex, edu- CLINICAL AND PATHOLOGICAL ANALYSES cation, the presence of APOE ε4 allele, or postmortem ␤ ␤ interval. Higher concentrations of total A and A 42, but The 3 clinical groups differed in Mini-Mental State Ex- not A␤ , correlated with lower MMSE scores (r=−0.62 Ͻ 40 amination (MMSE) scores (P .001), with the mAD group for both; P=.003 and .004) (Table 3). In addition, higher performing worse than both the NCI and MCI groups ␤ ␤ total A and A 42 concentrations correlated with worse (Table 1). Clinical diagnostic groups also differed in neuropathological scores (r=0.62-0.70; PϽ.01), as did CERAD diagnosis (P=.04), Braak staging (P=.04), and ␤ A 40 concentrations, although to a lesser extent (Table 3). the NIA-Reagan diagnosis (P=.02), with the mAD sub- Adjusting for age, partial correlation showed similar re- jects being more advanced neuropathologically com- sults, although it yielded smaller correlation coeffi- pared with both the MCI and NCI groups (Table 1). cients. There was no correlation between MLA binding Subjects with a CERAD diagnosis of AD (CERAD and A␤ protein concentrations. scoreϽ4; possible, probable, or definite AD; positive for cortical plaques) had lower MMSE scores (P=.06) and more advanced Braak stages and NIA-Reagan neuro- COMMENT pathologic diagnoses (P=.004 and PϽ.001) (Table 1) than the not AD group (CERAD score=4; no cortical plaques). This study examined SFC ␣7 nAChR binding and A␤ peptide concentrations across the clinical and neuro- MLA BINDING AND A␤ CONCENTRATIONS pathological categories of AD. Both markers were ACROSS CLINICAL AND assayed in the same samples of cortical tissue from sub- NEUROPATHOLOGICAL CATEGORIES jects who were clinically characterized within 12 months before death and neuropathologically evaluated The MLA binding levels were slightly higher in mAD sub- post mortem. We did not detect significant changes in jects; however, the difference was not statistically sig- SFC ␣7 nAChR binding across clinical diagnostic nificant (Table 2). Clinical groups differed in total A␤ groups. However, a trend toward elevated ␣7 nAChR ␤ ␤ ␤ (combined A 42 and A 40; P=.02) (Figure) and A 42 binding levels was evident in subjects with CERAD ␤ (P=.02), but not A 40, concentrations, with mAD sub- diagnoses of AD (possible, probable, or definite) rela- jects having the highest levels. tive to not AD subjects (without neuritic A␤ plaques). ␤ ␤ ␤ ␤ Subjects with a CERAD diagnosis of AD had higher Total A (sum of A 42 and A 40) and A 42 concentra- MLA binding (P=.08) (Figure) and higher concentrations were elevated in the CERAD-AD group compared ␤ ␤ ␤ tions of A 42 (P=.02), A 40 (P=.06), and total A (P=.02) with the CERAD–not AD group, as well as in the clini- (Table 2) (Figure) in SFC when compared with those with cal mAD compared with the MCI and NCI groups. The a CERAD diagnosis of not AD. increase in ␣7 nAChRs in A␤ plaque–positive subjects,

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5 5

4 4

3 3

2 2 MLA, fmol/mg of Protein

1 1

0 0 NCI MCI AD Not AD AD

C D 4000 4000

3000 3000

2000 2000 , pmol/g of Wet Tissue , pmol/g of Wet β

1000 1000 Total A Total

0 0

NCI MCI AD Not AD AD Clinical Diagnosis CERAD Diagnosis

Figure. ␣7 Nicotinic acetylcholine receptor binding (A and B) and total ␤-amyloid (A␤) peptide concentrations (C and D) in the frontal cortex from subjects categorized into clinical diagnostic groups of no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer disease (AD) (A and C) or into neuropathological groups of not AD and AD (possible, probable, or definite) by modified Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria (B and D). MLA indicates [3H]methyllycaconitine.

despite the lack of an association with A␤ concentra- includes not only insoluble fibrils in plaques, but also tions, indicates that cellular expression of this receptor soluble A␤ oligomers.41 The impact of these distinct pools is influenced, either directly or indirectly, by the pres- of A␤ on ␣7 nAChR binding in preclinical, early/ ence of senile plaques. This is in agreement with previ- moderate, and severe end-stage AD cases will be an im- ous studies in patients with AD and animal models34,35 portant question to answer in future studies. and is supported further by the current observation that There are several possible explanations for the ob- the correlation between ␣7 nAChR levels and neuro- served association between A␤ plaques and increased ␣7 pathological staging was stronger using NIA-Reagan cri- nAChR binding. Plaques may serve as reservoirs of soluble teria compared with Braak staging, the latter relying A␤ species,1 which can bind with high affinity to neu- only on neurofibrillary tangles for stage designation.30 ronal ␣7 receptors4,5 into a complex that is subse- The apparent stability of ␣7 nAChRs across clinical quently internalized.12 This may result in a compensa- categories of NCI, MCI, and mAD, and the lack of an as- tory increase in expression of ␣7 nAChR on the cell sociation with MMSE scores, could be explained by the surface. Additionally, excessive intracellular accumula- ␤ presence of plaques in all clinical groups. Cortical plaques tion of A 42 and subsequent neuronal lysis may contrib- were present in more than half of our NCI cases (Table 1), ute to plaque pathology,12 potentially creating a cycle of in agreement with previous reports of a substantial AD neuronal degeneration and A␤ plaque deposition in AD. pathology in cognitively normal aged individuals.28,36-40 High concentrations of fibrillar A␤ in plaques, or soluble Although these studies would benefit from examining A␤ in the vicinity of these structures, may also influ- larger numbers of cognitively intact subjects free of any ence the upregulation of ␣7 nAChR by reactive astro- A␤ pathology, such individuals are rare, as A␤ plaques cytes. Astrocytes proliferate and display increased ␣7 are a common feature in brains of elderly individu- nAChR density in the presence of A␤ plaques35,42,43 and als.36,37,39,40 Furthermore, the pathological burden of A␤ upregulate nAChR messenger RNA expression and pro-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 3. Association Between Clinical/Neuropathological Variables and Superior Frontal Cortex MLA Binding and A␤ ELISA Levels

r Value; P Value

MLA A␤40 A␤42 Total A␤ Variable (n=24) (n=20) (n=20) (n=20) Age, y NS 0.48; .03 0.56; .01 0.55; .01 Sex NS NS NS NS Education NS NS NS NS APOE ε4 NSNSNSNS MMSE −0.25; .26 −0.36; .12 −0.62; .004 −0.62; .003 PMI NS NS NS NS Braak stage 0.40; .053 0.36; .12 0.70; .001 0.62; .004 NIA-Reagan diagnosis −0.47; .02 −0.52; .02 −0.63; .003 −0.66; .001

Abbreviations: A␤, ␤-amyloid; ELISA, enzyme-linked immunosorbent assay; MLA, [3H]methyllycaconitine; MMSE, Mini-Mental State Examination; NIA, National Institute on Aging; NS, not statistically significant; PMI, postmortem interval; r, Spearman rank correlation coefficient.

tein levels when exposed to A␤ in vitro.44 Receptor bind- DeKosky. Acquisition of data: Ikonomovic, Wecker, and ing assays cannot differentiate the relative contribution DeKosky. Analysis and interpretation of data: Ikono- of different cell types to the overall regional expression movic, Wecker, Abrahamson, Wuu, Counts, Ginsberg, of ␣7 nAChRs detected in tissue homogenates. Adding Mufson, and DeKosky. Drafting of the manuscript: Ikono- to this complexity are the postsynaptic and presynaptic movic, Wecker, Abrahamson, Wuu, and Mufson. Criti- sites of expression of ␣7 nAChRs, involving both local cal revision of the manuscript for important intellectual con- neuronal circuitry and afferent projections from distant tent: Ikonomovic, Wecker, Abrahamson, Wuu, Counts, neuronal cell populations. In this regard, a recent single- Ginsberg, Mufson, and DeKosky. Statistical analysis: Wuu. cell expression profiling study demonstrated upregula- Obtained funding: Ikonomovic, Ginsberg, Mufson, and tion of ␣7 nAChR messenger RNA in cortical-project- DeKosky. Administrative, technical, and material sup- ing basal forebrain cholinergic neurons in mAD subjects,45 port: Ikonomovic, Wecker, Ginsberg, and DeKosky. Study suggesting that changes in cortical ␣7 protein levels in- supervision: Ikonomovic. volve presynaptic elements on an important cholinergic Financial Disclosure: None reported. afferent system. Collectively, these studies suggest that Funding/Support: This work was supported by NIA grants in SFC, ␣7 nAChR levels reported herein reflect changes AG14449 and AG10610. both in cortical-projecting cholinergic basal forebrain neu- Additional Contributions: Theresa Landers-Concatelli, rons and regional cell-specific expression of these recep- MS, and William R. Paljug, MS, provided expert techni- tors in response to A␤ pathology. cal assistance. We are indebted to the support of the par- In conclusion, the present findings demonstrate that ticipants in the Religious Orders Study; for a list of par- cognitive decline in mAD is not associated with detect- ticipating groups, see http://www.rush.edu/rumc able changes in cortical ␣7 nAChR binding levels. In con- /page-R12394.html. trast, A␤ concentrations increased in mAD and correlated with cognitive impairment, in accord with reported REFERENCES associations of increased A␤ load with cognitive decline 46,47 ␣ in AD. The observed trend for increased SFC 7in 1. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons subjects with plaques is in agreement with a previously from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007;8(2): reported positive correlation between ␣-bungarotoxin 101-112. binding and A␤ plaque density34 and warrants further in- 2. Newhouse PA, Potter P, Corwin J, Lenox R. Acute nicotinic blockade produces vestigation. 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