The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx of neurotoxic blood-derived debris, cells and microbial pathogens into the brain and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration.
This review by Sweeney and colleagues discusses the results of neuroimaging as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The mechanisms by which BBB breakdown leads to neuronal dysfunction and neurodegeneration are described. The importance of the BBB for therapeutic drug delivery and the adverse effects of BBB breakdown are noted, as well as opportunities to control the course of neurological diseases by targeting the BBB.
Sweeney MD, Sagare AP, Zlokovic BV: Blood-brain barrier breakdown in Alzheimer disease and neurodegenerative disorders. Nature Rev. Neurol. 14(3): 133-150 (2018).
“Schizophrenia is a disorder that involves hallucinations, delusions and cognitive impairment, and that affects nearly 1% of the global population. The mainstays of therapy have been drugs that block the activity of the D2 dopamine receptor (D2R), a member of the large G-protein-coupled receptor (GPCR) superfamily of membrane proteins. Unfortunately, most of these antipsychotic drugs come with a plethora of debilitating side effects, many of which are due to off-target interactions with other GPCRs. In a paper in Nature, Wang et al. now report the crystal structure of D2R in complex with the antipsychotic drug risperidone. The structure reveals features that might be useful for the design or discovery of drugs that have greater selectivity for D2R than existing therapeutics, and consequently have fewer side effects….”
Sibley DR and Shi L: A new era of rationally designed antipsychotics. Nature (News and Views, February 26, 2018).
“Flavonoids are a class of plant-derived dietary polyphenols that have attracted attention for their pro-cognitive and anti-inflammatory effects. The diversity of flavonoids and their extensive in vivo metabolism suggest that a variety of cellular targets in the brain are likely to be impacted by flavonoid consumption. Initially characterized as antioxidants, flavonoids are now believed to act directly on neurons and glia via the interaction with major signal transduction cascades, as well as indirectly via interaction with the blood-brain barrier and cerebral vasculature. This review discusses potential mechanisms of flavonoid action in the brain, with a focus on two critical transcription factors: cAMP response element-binding protein (CREB) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).”
The authors advocate bioavailability studies to verify the identity and concentration of flavonoid metabolites reaching the brain after ingestion and to validate that these metabolites are produced not just in rodent models but also in humans. Development of new cell lines may also provide a useful tool for investigation of the mechanisms of action of flavonoid metabolites in humans.
Jaeger BN, Parvlak SL, Gage FH: Mechanisms of dietary flavonoid action in neuronal function and neuroinflammation. Mol. Aspects Med.Nov 9, 2017. pii: S0098-2997(17)30111-5. doi: 10.1016/j.mam.2017.11.003.
The purpose of this study was to examine whether the APOE ε4 allele modifies the cognitive benefits of a multidomain lifestyle intervention. Participants (ages 60-77 years) were randomly assigned to a multidomain intervention group (diet, exercise, cognitive training, and vascular risk management) or a control group (general health advice). Intervention duration was 2 years. Group allocation was not actively disclosed to participants, and outcome assessors were masked to group allocation.
Results showed that APOE ε4 carriers and noncarriers were not significantly different at baseline, except for serum cholesterol level. The difference between the intervention and control groups in annual neuropsychological test battery total score change was 0.037 among carriers and 0.014 among noncarriers. Intervention effect was not significantly different between carriers and noncarriers.
The authors concluded that healthy lifestyle changes may be beneficial for cognition in older at-risk individuals even in the presence of APOE ε4 -related genetic susceptibility to dementia. Whether such benefits are more pronounced in APOE ε4 carriers compared with noncarriers needs to be further investigated. The authors also emphasized the importance of early prevention strategies that target multiple modifiable risk factors simultaneously.
Solomon A, Turunen H, Ngandu T, Peltonen M, Levälahti E, Helisalmi S, Antikainen R, Bäckman L, Hänninen T, Jula A, Laatikainen T, Lehtisalo J, Lindström J, Paajanen T, Pajala S, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M: Effect of the Apolipoprotein E Genotype on Cognitive Change During a Multidomain Lifestyle InterventionA Subgroup Analysis of a Randomized Clinical Trial. JAMA Neurol. [Epub ahead of print, January 22, 2018. doi:10.1001/jamaneurol.2017.4365].
“During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease.” Here, Mattson and colleagues consider how “intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood.” This metabolic switching appears to impact resistance of the brain to injury and disease.
Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A: Intermittent metabolic switching, neuroplasticity and brain health. Nature Rev. Neurosci. 19: 63-80 (2018).
A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. Faraco and colleagues report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase–dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut–brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. The authors suggest that the TH17 cell–IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt.
Faraco G, Brea D, Garcia-Bonilla L, Wang G, Racchumi G, Chang H, Buendia I, Santisteban MM, Segarra SG, Koizumi K, Sugiyama Y, Murphy M, Voss H, Anrather J, Iadecola C: Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nature Neurosci. 21: 240–249 (2018).
“Superconducting computing chips modelled after neurons can process information faster and more efficiently than the human brain. That achievement, described in Science Advances below, is a key benchmark in the development of advanced computing devices designed to mimic biological systems. And (as described below), it could open the door to more natural machine-learning software ….”
Schneider ML, Donnelly CA, Russek SE, Baek B, Pufall MR, Hopkins PF, Dresselhaus PD, Benz SP, Rippard WH: Ultralow power artificial synapses using nanotextured magnetic Josephson junctions. Science Advances 4(1): e1701329 (Jan 26, 2018); DOI: 10.1126/sciadv.1701329.
“During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease.” Here, Mattson and colleagues consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signaling pathways that promote neuroplasticity and resistance of the brain to injury and disease.
Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A: Intermittent metabolic switching, neuroplasticity and brain health. Nature Reviews Neuroscience 19: 63-80 (2018).