CSF and Brain Indices of Insulin Resistance, Oxidative Stress and Neuro-Inflammation in Early versus Late Alzheimer’s Disease

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.

Brain metabolic dysfunction at the core of Alzheimer's disease

“…Our finding that cytokines are activated early in AD but not late in the clinical course is consistent with previous observations [59,70]. It is particularly noteworthy that the pronounced reductions in cytokine activation overlapped with declines in the expression of trophic factor and mediators of insulin signaling/responsiveness, and increases in brain levels of AβPP-Aβ, pTau, and advanced glycation end-products [69]. Indeed, the complexity of cytokine activation profiles in AD CSF has been reported previously [71], perhaps due to time or disease duration related shifts in neuro-inflammation.…”

“…In a recent study, analysis of cerebrospinal fluid (CSF), ventricular fluid (VF) and postmortem brain tissue by multiplex bead-based ELISAs revealed either significantly or moderately elevated levels of at least 15 different cytokines in AD CSF and brains during early or intermediate stages of disease, but broad-based suppression rather than activation of pro-inflammatory mediators in VF and brain tissue during the late stages of AD [69]. Our finding that cytokines are activated early in AD but not late in the clinical course is consistent with previous observations [59,70].…”

Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease

“…Downstream effects include oxidative stress with increased production of reactive oxygen and reactive nitrogen species which can damage nerve terminals, causing synaptic dysfunction and attendant cognitive impairment [19]. Furthermore, since chronic inflammation is known to exacerbate insulin resistance associated with systemic disease-states [24–28], neuro-inflammation could also have an important etiopathic role in the brain insulin and IGF-1 resistances that occur in AD [29–34] and Parkinson’s disease [35]. Furthermore, inflammation has inhibitory effects on incretin (orexin) expression and function, while reduced insulin resistance afforded by activation of incretin signaling inhibits pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) [36].…”

“…Experimental models have shown that brain insulin resistance or deficiency impair learning and memory [64]. In early or intermediate stages of AD, brain and CSF levels of insulin are decreased [34], while Aβ42 and advanced glycation end-products are increased [34, 54, 93]. High levels of Aβ42 in brain and CSF are associated with low levels in serum due to decreased clearance [94].…”

Insulin resistance in Alzheimer's disease

“…A recent and prominent concern has been the role of IR as a factor promoting oxidative stress in the pathogenetic cascade of AD [105, 106]. The term “oxidative stress” refers to an imbalanced biochemical state wherein the cell is producing more reactive oxygen species than its antioxidant activity can withstand [107].…”