Cerebrospinal fluid soluble insulin receptor levels in Alzheimer's disease.

INTRODUCTION: Brain insulin resistance and deficiency is a consistent feature of Alzheimer's disease (AD). Insulin resistance can be mediated by the surface expression of the insulin receptor (IR). Cleavage of the IR generates the soluble IR (sIR). METHODS: We measured the levels of sIR present in cerebrospinal fluid (CSF) from individuals along the AD diagnostic spectrum from two cohorts: Seattle (n = 58) and the Consortium for the Early Identification of Alzheimer's Disease-Quebec (CIMA-Q; n = 61). We further investigated the brain cellular contribution for sIR using human cell lines. RESULTS: CSF sIR levels were not statistically different in AD. CSF sIR and amyloid beta (Aß)42 and Aß40 levels significantly correlated as well as CSF sIR and cognition in the CIMA-Q cohort. Human neurons expressing the amyloid precursor protein "Swedish" mutation generated significantly greater sIR and human astrocytes were also able to release sIR in response to both an inflammatory and insulin stimulus. DISCUSSION: These data support further investigation into the generation and role of sIR in AD. Highlights: Cerebrospinal fluid (CSF) soluble insulin receptor (sIR) levels positively correlate with amyloid beta (Aß)42 and Aß40.CSF sIR levels negatively correlate with cognitive performance (Montreal Cognitive Assessment score).CSF sIR levels in humans remain similar across Alzheimer's disease diagnostic groups.Neurons derived from humans with the "Swedish" mutation in which Aß42 is increased generate increased levels of sIR.Human astrocytes can also produce sIR and generation is stimulated by tumor necrosis factor α and insulin.

Role of Retinoid X Receptors (RXRs) and dietary vitamin A in Alzheimer's disease: Evidence from clinicopathological and preclinical studies.

BACKGROUND: Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of ß-amyloid peptides (Aß), and could thus contribute to the onset of AD. METHODS: We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor ß (RARß) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20). RESULTS: The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aß40 and Aß42, as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal Aß load. However, the expression of Rxr-ß in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aß in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARß levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex. CONCLUSION: Our data suggest that (i) an altered expression of RXRs receptors is a contributor to ß-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females.

Can Natural Products Exert Neuroprotection without Crossing the Blood-Brain Barrier?

The scope of evidence on the neuroprotective impact of natural products has been greatly extended in recent years. However, a key question that remains to be answered is whether natural products act directly on targets located in the central nervous system (CNS), or whether they act indirectly through other mechanisms in the periphery. While molecules utilized for brain diseases are typically bestowed with a capacity to cross the blood-brain barrier, it has been recently uncovered that peripheral metabolism impacts brain functions, including cognition. The gut-microbiota-brain axis is receiving increasing attention as another indirect pathway for orally administered compounds to act on the CNS. In this review, we will briefly explore these possibilities focusing on two classes of natural products: omega-3 polyunsaturated fatty acids (n-3 PUFAs) from marine sources and polyphenols from plants. The former will be used as an example of a natural product with relatively high brain bioavailability but with tightly regulated transport and metabolism, and the latter as an example of natural compounds with low brain bioavailability, yet with a growing amount of preclinical and clinical evidence of efficacy. In conclusion, it is proposed that bioavailability data should be sought early in the development of natural products to help identifying relevant mechanisms and potential impact on prevalent CNS disorders, such as Alzheimer's disease.