title: Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer's disease.
abstract: BACKGROUND
  Reduction of precuneus choline acetyltransferase activity co-occurs with greater beta-amyloid (Aβ) in Alzheimer's disease (AD). Whether this cholinergic deficit is associated with alteration in nerve growth factor (NGF) signaling and its relation to Aβ plaque and neurofibrillary tangle (NFT) pathology during disease onset is unknown.
  
  
  METHODS
  Precuneus NGF upstream and downstream signaling levels relative to Aβ and NFT pathology were evaluated using biochemistry and histochemistry in 62 subjects with a premortem diagnosis of non-cognitively impaired (NCI; n = 23), mild cognitive impairment (MCI; n = 21), and mild to moderate AD (n = 18).
  
  
  RESULTS
  Immunoblots revealed increased levels of proNGF in AD subjects but not MCI subjects, whereas cognate receptors were unchanged. There were no significant differences in protein level for the downstream survival kinase-signaling proteins Erk and phospho-Erk among groups. Apoptotic phospho-JNK, phospho-JNK/JNK ratio, and Bcl-2 were significantly elevated in AD subjects. Soluble Aβ1-42 and fibrillar Aβ measured by [(3)H] Pittsburgh compound-B ([(3)H]PiB) binding were significantly higher in AD subjects compared with MCI and NCI subjects. The density of plaques showed a trend to increase, but only 6-CN-PiB-positive plaques reached significance in AD subjects. AT8-positive, TOC-1-positive, and Tau C3-positive NFT densities were unchanged, whereas only AT8-positive neuropil thread density was statistically higher in AD subjects. A negative correlation was found between proNGF, phospho-JNK, and Bcl-2 levels and phospho-JNK/JNK ratio and cognition, whereas proNGF correlated positively with 6-CN-PiB-positive plaques during disease progression.
  
  
  CONCLUSIONS
  Data indicate that precuneus neurotrophin pathways are resilient to amyloid toxicity during the onset of AD.
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
authors: Sylvia E
authors: SE
authors: Perez
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
authors: Bin
authors: B
authors: He
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
authors: Muhammad
authors: M
authors: Nadeem
authors: Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida.
authors: Joanne
authors: J
authors: Wuu
authors: Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, Kentucky.
authors: Stephen W
authors: SW
authors: Scheff
authors: Departments of Neurology and Psychiatry, University of Pittsburgh; Geriatric Research Center, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.
authors: Eric E
authors: EE
authors: Abrahamson
authors: Departments of Neurology and Psychiatry, University of Pittsburgh; Geriatric Research Center, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.
authors: Milos D
authors: MD
authors: Ikonomovic
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois. Electronic address: emufson@rush.edu.
authors: Elliott J
authors: EJ
authors: Mufson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000814:Aniline Compounds / Q000493:pharmacokinetics; D002795:Choline O-Acetyltransferase; D060825:Cognitive Dysfunction / Q000473:pathology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008609:Mental Status Schedule; D020932:Nerve Growth Factor / Q000378:metabolism*; D019600:Neuropil Threads / Q000473:pathology; D010296:Parietal Lobe / Q000378:metabolism*; D062706:Prodromal Symptoms; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018709:Statistics, Nonparametric; D013844:Thiazoles / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D014316:Tritium; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase
keywords: Alzheimer’s disease; Amyloid; Mild cognitive impairment; Neuropathology; Neurotrophic factors; Tau