Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction.
Senatorov Vladimir V,Friedman Aaron R,Milikovsky Dan Z,Ofer Jonathan,Saar-Ashkenazy Rotem,Charbash Adiel,Jahan Naznin,Chin Gregory,Mihaly Eszter,Lin Jessica M,Ramsay Harrison J,Moghbel Ariana,Preininger Marcela K,Eddings Chelsy R,Harrison Helen V,Patel Rishi,Shen Yishuo,Ghanim Hana,Sheng Huanjie,Veksler Ronel,Sudmant Peter H,Becker Albert,Hart Barry,Rogawski Michael A,Dillin Andrew,Friedman Alon,Kaufer Daniela
Science translational medicine
Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the life span. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor-β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology in rodents. Specifically, infusion of the serum protein albumin into the young rodent brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors or pharmacological inhibition of TGFβ signaling reversed these symptomatic outcomes in aged mice. Last, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging and demonstrates that the aging brain may retain considerable latent capacity, which can be revitalized by therapeutic inhibition of TGFβ signaling.
Revisiting How the Brain Senses Glucose-And Why.
Bentsen Marie Aare,Mirzadeh Zaman,Schwartz Michael W
Glucose-sensitive neurons have long been implicated in glucose homeostasis, but how glucose-sensing information is used by the brain in this process remains uncertain. Here, we propose a model in which (1) information relevant to the circulating glucose level is essential to the proper function of this regulatory system, (2) this input is provided by neurons located outside the blood-brain barrier (BBB) (since neurons situated behind the BBB are exposed to glucose in brain interstitial fluid, rather than that in the circulation), and (3) while the efferent limb of this system is comprised of neurons situated behind the BBB, many of these neurons are also glucose sensitive. Precedent for such an organizational scheme is found in the thermoregulatory system, which we draw upon in this framework for understanding the role played by brain glucose sensing in glucose homeostasis.
How and why do T cells and their derived cytokines affect the injured and healthy brain?
Filiano Anthony J,Gadani Sachin P,Kipnis Jonathan
Nature reviews. Neuroscience
The evolution of adaptive immunity provides enhanced defence against specific pathogens, as well as homeostatic immune surveillance of all tissues. Despite being 'immune privileged', the CNS uses the assistance of the immune system in physiological and pathological states. In this Opinion article, we discuss the influence of adaptive immunity on recovery after CNS injury and on cognitive and social brain function. We further extend a hypothesis that the pro-social effects of interferon-regulated genes were initially exploited by pathogens to increase host-host transmission, and that these genes were later recycled by the host to form part of an immune defence programme. In this way, the evolution of adaptive immunity may reflect a host-pathogen 'arms race'.
Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes.
Bolo Nicolas R,Jacobson Alan M,Musen Gail,Keshavan Matcheri S,Simonson Donald C
The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton MRS, we measured glutamate concentrations in ACC and occipital lobe cortex (OCC) in 13 subjects with T1D without major depression (HbA 7.1 ± 0.7% [54 ± 7 mmol/mol]) and 11 healthy control subjects without diabetes (HbA 5.5 ± 0.2% [37 ± 3 mmol/mol]) during fasting euglycemia followed by a 60-min +5.5 mmol/L hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level-dependent functional MRI to measure the fractional amplitude of low-frequency fluctuations in slow-4 band (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (emotional Stroop task, self-referent encoding task [SRET]) and clinical ratings (Hamilton Depression Rating Scale [HAM-D], Symptom Checklist-90 Revised [SCL-90-R]), respectively. During HG, ACC glutamate increased (1.2 mmol/kg, 10% = 0.014) while ACC fALFF4 was unchanged (-0.007, -2%, = 0.449) in the T1D group; in contrast, glutamate was unchanged (-0.2 mmol/kg, -2%, = 0.578) while fALFF4 decreased (-0.05, -13%, = 0.002) in the control group. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative word response times ( = 0.017) and higher depression rating scores (HAM-D = 0.020, SCL-90-R depression = 0.008). Higher glutamate change tended to associate with longer emotional Stroop response times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia because of the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations among chronic hyperglycemia, cortical thinning, and depressive symptoms in T1D.
Potential Biochemical Mechanisms of Brain Injury in Diabetes Mellitus.
Ma Wei-Xing,Tang Jing,Lei Zhi-Wen,Li Chun-Yan,Zhao Li-Qing,Lin Chao,Sun Tao,Li Zheng-Yi,Jiang Ying-Hui,Jia Jun-Tao,Liang Cheng-Zhu,Liu Jun-Hong,Yan Liang-Jun
Aging and disease
The goal of this review was to summarize current biochemical mechanisms of and risk factors for diabetic brain injury. We mainly summarized mechanisms published in the past three years and focused on diabetes induced cognitive impairment, diabetes-linked Alzheimer's disease, and diabetic stroke. We think there is a need to conduct further studies with increased sample sizes and prolonged period of follow-ups to clarify the effect of DM on brain dysfunction. Additionally, we also think that enhancing experimental reproducibility using animal models in conjunction with application of advanced devices should be considered when new experiments are designed. It is expected that further investigation of the underlying mechanisms of diabetic cognitive impairment will provide novel insights into therapeutic approaches for ameliorating diabetes-associated injury in the brain.