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Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer's disease.

ABSTRACT: Reduction of precuneus choline acetyltransferase activity co-occurs with greater beta-amyloid (A?) in Alzheimer's disease (AD). Whether this cholinergic deficit is associated with alteration in nerve growth factor (NGF) signaling and its relation to A? plaque and neurofibrillary tangle (NFT) pathology during disease onset is unknown.Precuneus NGF upstream and downstream signaling levels relative to A? 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).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 A?1-42 and fibrillar A? 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.Data indicate that precuneus neurotrophin pathways are resilient to amyloid toxicity during the onset of AD.

SUBMITTER: Perez SE

PROVIDER: S-EPMC4096429 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer's disease.

Perez Sylvia E SE He Bin B Nadeem Muhammad M Wuu Joanne J Scheff Stephen W SW Abrahamson Eric E EE Ikonomovic Milos D MD Mufson Elliott J EJ

Biological psychiatry 20140111 8

<h4>Background</h4>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.<h4>Methods</h4>Precuneus NGF upstream and downstream signaling levels relative to Aβ and NFT pathology were evaluated using biochemistry and hist ...[more]

PMID: 24529280

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Project description:OBJECTIVE:To investigate the multifactorial processes underlying cognitive aging based on the hypothesis that multiple causal pathways and mechanisms (amyloid, vascular, and resilience) influence longitudinal cognitive decline in each individual through worsening brain health. METHODS:We identified 1,230 elderly subjects (aged ?50?years) with an average of 4.9?years of clinical follow-up and with amyloid positron emission tomography, diffusion tensor imaging, and structural magnetic resonance imaging scans from the population-based Mayo Clinic Study of Aging. We examined imaging markers of amyloid and brain health (white matter microstructural integrity and cortical thinning), systemic vascular health preceding the imaging markers, and early to midlife intellectual enrichment to predict longitudinal cognitive trajectories. We used latent growth curve models for modeling longitudinal cognitive decline. RESULTS:All the pathways (amyloid, vascular, resilience) converged through their effects on cortical thinning and worsening cognition and together explained patterns in cognitive decline. Resilience and vascular pathways (aging process, sex differences, education/occupation, and systemic vascular health) had significant impact on white matter microstructural integrity. Education/occupation levels contributed to white matter integrity through systemic vascular health. Worsening white matter integrity contributed to significant cortical thinning and subsequently longitudinal cognitive decline. Baseline amyloidosis contributed to a significant proportion of cognitive decline that accelerated with longer follow-up times, and its primary impact was through cortical thinning. INTERPRETATION:We developed an integrated framework to help explain the dynamic and complex process of cognitive aging by considering key causal pathways. Such an approach is important for both better comprehension of cognitive aging processes and will aid in the development of successful intervention strategies. ANN NEUROL 2019;86:866-877.

Dataset Information

Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer's disease.

Publications

Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer's disease.

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