Cross-species comparative hippocampal transcriptomics in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial pathology, with most cases having a sporadic origin. Recently, knock-in (KI) mouse models, such as the novel humanized amyloid-ß (hAß)-KI, have been developed to better resemble sporadic human AD. METHODS: Here, we compared hippocampal publicly available transcriptomic profiles of transgenic (5xFAD and APP/PS1) and KI (hAß-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. RESULTS: The three mouse models presented more Gene Ontology biological processes terms and enriched signaling pathways in common with LOAD than with EOAD individuals. Experimental validation of consistently dysregulated genes revealed five altered in mice (SLC11A1, S100A6, CD14, CD33, and C1QB) and three in humans (S100A6, SLC11A1, and KCNK). Finally, we identified 17 transcription factors potentially acting as master regulators of AD. CONCLUSION: Our cross-species analyses revealed that the three mouse models presented a remarkable similarity to LOAD, with the hAß-KI being the more specific one.

Association of the fibronectin type III domain-containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans.

Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-ß deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-ß PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-ß42, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.

Oxytocin attenuates microglial activation and restores social and non-social memory in APP/PS1 Alzheimer model mice.

Alzheimer's disease (AD) is characterized by neurodegeneration, memory loss, and social withdrawal. Brain inflammation has emerged as a key pathogenic mechanism in AD. We hypothesized that oxytocin, a pro-social hypothalamic neuropeptide with anti-inflammatory properties, could have therapeutic actions in AD. Here, we investigated oxytocin expression in experimental models of AD, and evaluated the therapeutic potential of treatment with oxytocin. Amyloid-ß peptide oligomers (AßOs) reduced oxytocin expression in vitro and in vivo, and treatment with oxytocin prevented microglial activation induced by AßOs in purified microglial cultures. Treatment of aged APP/PS1 mice, a mouse model of AD, with intranasal oxytocin attenuated microglial activation and favored deposition of Aß in dense core plaques, a potentially neuroprotective mechanism. Remarkably, treatment with oxytocin alleviated social and non-social memory impairments in aged APP/PS1 mice. Our findings point to oxytocin as a potential therapeutic target to reduce brain inflammation and correct memory deficits in AD.

Brain FNDC5/Irisin Expression in Patients and Mouse Models of Major Depression.

Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a comorbidity and a risk factor for Alzheimer's disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5/irisin expression is altered in depression remains elusive. Here, we investigate changes in fndc5 expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreased fndc5 expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that the induction of depressive-like behavior in male mice by lipopolysaccharide decreased fndc5 expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased fndc5 expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in altered fndc5 expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increased fndc5 gene expression in the mouse frontal cortex. Results indicate a region-specific modulation of fndc5 in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortex fndc5 expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction in fndc5 mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathologic mechanism between MDD and AD.

How does the skeletal muscle communicate with the brain in health and disease?

Endocrine mechanisms have been largely associated with metabolic control and tissue cross talk in mammals. Classically, myokines comprise a class of signaling proteins released in the bloodstream by the skeletal muscle, which mediate physiological and metabolic responses in several tissues, including the brain. Recent exciting evidence suggests that myokines (e.g. cathepsin B, FNDC5/irisin, interleukin-6) act to control brain functions, including learning, memory, and mood, and may mediate the beneficial actions of physical exercise in the brain. However, the intricate mechanisms connecting peripherally released molecules to brain function are not fully understood. Accumulating findings further indicates that impaired skeletal muscle homeostasis impacts brain metabolism and physiology. Here we review recent findings that suggest that muscle-borne signals are essential for brain physiology and discuss perspectives on how these signals vary in response to exercise or muscle diseases. Understanding the complex interactions between skeletal muscle and brain may result in more effective therapeutic strategies to expand healthspan and to prevent brain disease. This article is part of the special Issue on 'Cross Talk between Periphery and the Brain'.

Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease.

Alzheimer's disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.

Connecting Alzheimer's disease to diabetes: Underlying mechanisms and potential therapeutic targets.

Alzheimer's disease (AD) is a risk factor for type 2 diabetes and vice versa, and a growing body of evidence indicates that these diseases are connected both at epidemiological, clinical and molecular levels. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and type 2 diabetes. Impaired neuronal insulin signaling and endoplasmic reticulum (ER) stress are present in animal models of AD, similar to observations in peripheral tissue in T2D. These findings shed light into novel diabetes-related mechanisms leading to brain dysfunction in AD. Here, we review the literature on selected mechanisms shared between these diseases and discuss how the identification of such mechanisms may lead to novel therapeutic targets in AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'