Abstract
Alzheimer’s disease (AD) is characterized by progressive impairments in cognitive and behavioral functions with deficits in learning, memory and executive reasoning. Growing evidence points toward brain insulin and insulin-like growth factor (IGF) resistance-mediated metabolic derangements as critical etiologic factors in AD. This suggests that indices of insulin/IGF resistance and their consequences, i.e. oxidative stress, neuro-inflammation, and reduced neuronal plasticity, should be included in biomarker panels for AD. Herein, we examine a range of metabolic, inflammatory, stress, and neuronal plasticity related proteins in early AD, late AD, and aged control postmortem brain, postmortem ventricular fluid (VF), and clinical cerebrospinal fluid (CSF) samples. In AD brain, VF, and CSF samples the trends with respect to alterations in metabolic, neurotrophin, and stress indices were similar, but for pro-inflammatory cytokines, the patterns were discordant. With the greater severities of dementia and neurodegeneration, the differences from control were more pronounced for late AD (VF and brain) than early or moderate AD (brain, VF and CSF). The findings suggest that the inclusion of metabolic, neurotrophin, stress biomarkers in AβPP-Aβ+pTau CSF-based panels could provide more information about the status and progression of neurodegeneration, as well as aid in predicting progression from early- to late-stage AD. Furthermore, standardized multi-targeted molecular assays of neurodegeneration could help streamline postmortem diagnoses, including assessments of AD severity and pathology.
Highlights
Growing evidence supports the concept that in Alzheimer’s disease (AD), metabolic dysfunction, mediated by impairments in insulin and insulin-like growth factor (IGF) signaling [1,2,3,4,5,6,7,8,9,10,11,12], causes progressive deficits in brain glucose utilization, energy metabolism, cytoskeleton and myelin maintenance, and neuronal plasticity [13,14]
Direct-binding Enzyme-linked immunosorbent assay (ELISA) results for pTau, AβPP, AβPP-Aβ, 4-HNE, 8-OHdG, and advanced glycation end-products (AGE) were analyzed with respect to Braak AD stage (Figure 1)
Data from neuroimaging and human brain studies strongly suggest that CNS metabolic indices, those related to brain insulin signaling, could help with early detection of AD, monitoring the clinical course, and evaluating responses to treatment
Summary
Growing evidence supports the concept that in Alzheimer’s disease (AD), metabolic dysfunction, mediated by impairments in insulin and insulin-like growth factor (IGF) signaling [1,2,3,4,5,6,7,8,9,10,11,12], causes progressive deficits in brain glucose utilization, energy metabolism, cytoskeleton and myelin maintenance, and neuronal plasticity [13,14]. The pivotal roles of insulin and IGF-1 resistance as mediators of cognitive impairment and neurodegeneration have been well documented in humans and experimental animals [7,11,12,17]. This concept is corroborated by the findings that cognitive impairment and neurodegeneration can be slowed, reduced in severity, or prevented in experimental animals and humans by treatment with insulin sensitizer agents, insulin, or long-acting glucagon-like peptide-1 (GLP-1)-related compounds [18,19,20,21,22,23,24,25,26,27]
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