Middle-aged Brain Research Articles

Reduced neural distinctiveness of speech representations in the middle-aged brain.

Speech perception declines independent of hearing thresholds in middle-age, and the neurobiological reasons are unclear. In line with the age-related neural dedifferentiation hypothesis, we predicted that middle-aged adults show less distinct cortical representations of phonemes and acoustic-phonetic features relative to younger adults. In addition to an extensive audiological, auditory electrophysiological, and speech perceptual test battery, we measured electroencephalographic responses time-locked to phoneme instances (phoneme-related potential; PRP) in naturalistic, continuous speech and trained neural network classifiers to predict phonemes from these responses. Consistent with age-related neural dedifferentiation, phoneme predictions were less accurate, more uncertain, and involved a broader network for middle-aged adults compared with younger adults. Representational similarity analysis revealed that the featural relationship between phonemes was less robust in middle-age. Electrophysiological and behavioral measures revealed signatures of cochlear neural degeneration (CND) and speech perceptual deficits in middle-aged adults relative to younger adults. Consistent with prior work in animal models, signatures of CND were associated with greater cortical dedifferentiation, explaining nearly a third of the variance in PRP prediction accuracy together with measures of acoustic neural processing. Notably, even after controlling for CND signatures and acoustic processing abilities, age-group differences in PRP prediction accuracy remained. Overall, our results reveal "fuzzier" phonemic representations, suggesting that age-related cortical neural dedifferentiation can occur even in middle-age and may underlie speech perceptual challenges, despite a normal audiogram.

Increase in activin A may counteract decline in synaptic plasticity with age.

Activin A, a member of the transforming growth factor β (TGF-β) family, is widely recognized for its neurotrophic and neuroprotective function in the developing and injured brain, respectively. Moreover, in the healthy adult brain, activin A has been shown to tune signal processing at excitatory synapses in a fashion that improves cognitive performance. Because its level in human cerebrospinal fluid rises with age, we wondered whether activin A has a role in mitigating the gradual cognitive decline that healthy individuals experience in late-life. To interrogate the role of activin A in synaptic plasticity in the aging brain, we used an established transgenic mouse line, in which expression of a dominant-negative mutant of activin receptor IB (dnActRIB) serves to disrupt activin receptor signaling in a forebrain-specific fashion. In brain slices of young adult dnActRIB mice (2-4 months old), the NMDA receptor-dependent and -independent forms of long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapse of the hippocampus were equally impaired relative to the extent of LTP measured in the wild-type preparation. Unexpectedly, the difference between the genotypes disappeared when the two forms of LTP were re-examined in slices from middle-aged mice (13-16 months old). Since the level of activin A and endogenous ActRIB both displayed a significant elevation in middle-aged hippocampus, we reasoned that with such a rise, the dominant-negative effect of the mutant receptors could be overcome. Substantiating this idea, we found that administration of recombinant activin A was indeed capable of restoring full-blown LTP in slices from young dnActRIB mice. Our data suggest that, beginning in the middle-aged brain, endogenous activin receptor signaling appears to become strengthened in an attempt to stave off cognitive decline. If further corroborated, this concept would also hold promise for new therapeutic venues to preserve cognitive functions in the aged brain.

TonEBP Haploinsufficiency Attenuates Microglial Activation and Memory Deficits in Middle-Aged and Amyloid β Oligomer-Treated Mice.

Age-related microglial activation is associated with cognitive impairment. Tonicity-responsive enhancer-binding protein (TonEBP) is a critical mediator of microglial activation in response to neuroinflammation. However, the precise role of TonEBP in the middle-aged brain is not yet known. We used TonEBP haploinsufficient mice to investigate the role of TonEBP in middle-aged or amyloid β oligomer (AβO)-injected brains and examined the effect of TonEBP knockdown on AβO-treated BV2 microglial cells. Consistent with an increase in microglial activation with aging, hippocampal TonEBP expression levels were increased in middle-aged (12-month-old) and old (24-month-old) mice compared with young (6-month-old) mice. Middle-aged TonEBP haploinsufficient mice showed reduced microglial activation and fewer memory deficits than wild-type mice. Electron microscopy revealed that synaptic pruning by microglial processes was reduced by TonEBP haploinsufficiency. TonEBP haploinsufficiency also reduced dendritic spine loss and improved memory deficits in AβO-treated mice. Furthermore, TonEBP knockdown attenuated migration and phagocytosis in AβO-treated BV2 cells. These findings suggest that TonEBP plays important roles in age-related microglial activation and memory deficits.

Estradiol and the Catechol-o-methyltransferase Gene Interact to Predict Working Memory Performance: A Replication and Extension.

Decades of evidence across taxa have established the importance of dopamine (DA) signaling in the pFC for successful working memory performance. Genetic and hormonal factors can shape individual differences in prefrontal DA tone. The catechol-o-methyltransferase (COMT) gene regulates basal prefrontal DA, and the sex hormone 17β-estradiol potentiates DA release. E. Jacobs and M. D'Esposito [Estrogen shapes dopamine-dependent cognitive processes: Implications for women's health. Journal of Neuroscience, 31, 5286-5293, 2011] investigated the moderating role of estradiol on cognition using the COMT gene and COMT enzymatic activity as a proxy for pFC DA tone. They found that increases in 17β-estradiol within women at two time points during the menstrual cycle influenced working memory performance in a COMT-dependent manner. Here, we aimed to replicate and extend the behavioral findings of Jacobs and D'Esposito by employing an intensive repeated-measures design across a full menstrual cycle. Our results replicated the original investigation. Within-person increases in estradiol were associated with improved performance on 2-back lure trials for participants with low basal levels of DA (Val/Val carriers). The association was in the opposite direction for participants with higher basal levels of DA (Met/Met carriers). Our findings support the role of estrogen in DA-related cognitive functions and further highlight the need to consider gonadal hormones in cognitive science research.

Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain

BackgroundNeuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer’s disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD.MethodsSixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers.ResultsAdministration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS.ConclusionsColitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

Early stem cell aging in the mature brain.

Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell behavior represent early targets to promote tissue function later in life. Here, we pinpoint multiple factors that disrupt neural stem cell (NSC) behavior in the adult hippocampus. Clonal tracing showed that NSCs exhibit asynchronous depletion by identifying short-term NSCs (ST-NSCs) and long-term NSCs (LT-NSCs). ST-NSCs divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent LT-NSCs are maintained for months but are pushed out of homeostasis by lengthening quiescence. Single-cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of molecular aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC aging factor. Treatment with the Abl inhibitor imatinib increased NSC activation without impairing NSC maintenance in the middle-aged brain. Our study indicates that hippocampal NSCs are particularly vulnerable and adaptable to cellular aging.

Different responses after intracerebral hemorrhage between young and early middle-aged mice

Although aging is a major risk factor for intracerebral hemorrhage (ICH), there are very few studies comparing ICH pathology between young and early middle-aged mice. In this study, 8-month old mice (early middle-aged mice) were compared against 2-month old mice (young mice) in neurological and histological changes after ICH induction, such as body weight, lesion volume, astrocytic responses, and motor and cognitive functions. At day 8 after ICH, there was no significant difference in lesion volume between the two groups, and both groups did not exhibit significant cognitive decline, as assessed by spontaneous alternative Y-maze test. On the other hand, 8-month old mice showed delayed recovery from body weight loss, along with reduced astrocytic activation. Interestingly, in the two motor function tests (beam-walking test and corner turn test), 8-month old mice exhibited lower scores only in the beam-walking test, suggesting a partial disturbance in motor recovery after ICH. These results suggest that age-related differences in ICH pathology may already start to appear in early middle-aged brains.

Chronic depression-like phenotype in male offspring mice following perinatal exposure to naturally contaminated eels with a mixture of organic and inorganic pollutants.

Previously, we demonstrated that maternal exposure to high, intermediate, or lowly contaminated European eels with a mixture of chemicals, during pregnancy and lactation, resulted in adult despair-like behavior, selectively in male offspring mice. Here, we investigate if depression-like behavior in offspring males was transient or permanent by monitoring immobility behavior, a measure of behavioral despair, at three distinct stages of life, including young adult (post-natal day (PND) 55), mature adult (PND 200) and middle (PNDs 335-336) age, in the forced swimming (FST) and the tail suspension (TST) tests. Oxidative stress markers including malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were evaluated in the hippocampus, prefrontal cortex, and cerebellum of middle-aged animals. Findings showed a significant enhancement of immobility behavior in the TST performed at young adult age (all p < 0.05) in the FST carried out at mature adult age (all p < 0.001) and in both behavioral tests realized at middle age (all p < 0.05, except one p = 0.06) in mice perinatally exposed to eels compared with non-exposed controls. Antioxidant-related enzyme activities, including SOD and CAT, were only elevated in the hippocampus of middle-aged males perinatally exposed to the two more polluted eels (all p < 0.05). Further, lipid peroxidation, assessed by MDA levels, was not found to be differentially regulated in the selected areas of middle-aged brains of exposed mice (all p > 0.05). Collectively, this suggested limited oxidative metabolism disturbances in middle-aged brains exposed to eels. In summary, our results highlighted that offspring males perinatally exposed to naturally contaminated reared and river eels with persistent organic pollutants (POPs) and heavy metals displayed chronic depression-like phenotype. As extrapolation of data to humans should be done with precaution, retrospective and prospective epidemiological studies are needed to clarify this potential relationship, stressed in our animal model, between maternal polluted fish consumption and chronically low mood in offspring.

Loss of NF-\u03baB p50 function synergistically augments microglial priming in the middle-aged brain

BackgroundWhile NF-κB p50 function is impaired in central nervous system disease, aging in non-CNS tissues, and response to reactive oxygen species, the role of NF-κB p50 in aging-associated microglial pro-inflammatory priming is poorly understood.MethodsMale NF-κB p50+/+ and NF-κB p50−/− mice at three different ages (1.5–3.0 month old, 8.0–11.0 month old, and 16.0–18.0 month old) were treated with LPS (5 mg/kg, IP) to trigger peripheral inflammation, where circulating cytokines, neuroinflammation, microglia morphology, and NF-κB p50/p65 function in brain tissue were determined 3 h later.ResultsPeripheral LPS injection in 9-month-old C57BL/6 mice resulted in lower NF-κB p50 DNA binding of nuclear extracts from the whole brain, when compared to 3-week-old C57BL/6 mice, revealing differences in LPS-induced NF-κB p50 activity in the brain across the mouse lifespan. To examine the consequences of loss NF-κB p50 function with aging, NF-κB p50+/+ and NF-κB p50−/− mice of three different age groups (1.5–3.0 month old, 8.0–11.0 month old, and 16.0–18.0 month old) were injected with LPS (5 mg/kg, IP). NF-κB p50−/− mice showed markedly elevated circulating, midbrain, and microglial TNFα when compared to NF-κB p50+/+ mice at all ages. Notably, the 16.0–18.0-month-old (middle aged) NF-κB p50−/− mice exhibited synergistically augmented LPS-induced serum and midbrain TNFα when compared to the younger (1.5–3.0 month old, young adult) NF-κB p50−/− mice. The 16.0–18.0-month-old LPS-treated NF-κB p50−/− mice also had the highest midbrain IL-1β expression, largest number of microglia with changes in morphology, and greatest elevation of pro-inflammatory factors in isolated adult microglia. Interestingly, aging NF-κB p50−/− mice exhibited decreased brain NF-κB p65 expression and activity.ConclusionsThese findings support that loss of NF-κB p50 function and aging in middle-aged mice may interact to excessively augment peripheral/microglial pro-inflammatory responses and point to a novel neuroinflammation signaling mechanism independent the NF-κB p50/p65 transcription factor in this process.

Global quantitative TPA-based proteomics of mouse brain structures reveals significant alterations in expression of proteins involved in neuronal plasticity during aging

Aging is believed to be the result of alterations of protein expression and accumulation of changes in biomolecules. Although there are numerous reports demonstrating changes in protein expression in brain during aging, only few of them describe global changes at the protein level. Here, we present the deepest quantitative proteomic analysis of three brain regions, hippocampus, cortex and cerebellum, in mice aged 1 or 12 months, using the total protein approach technique. In all the brain regions, both in young and middle-aged animals, we quantitatively measured over 5,200 proteins. We found that although the total protein expression in middle-aged brain structures is practically unaffected by aging, there are significant differences between young and middle-aged mice in the expression of some receptors and signaling cascade proteins proven to be significant for learning and memory formation. Our analysis demonstrates that the hippocampus is the most variable structure during natural aging and that the first symptoms of weakening of neuronal plasticity may be observed on protein level in middle-aged animals.

Hippocampal-dependent memory deficit induced by perinatal exposure to polutted eels in middle-aged offspring mice: Sex differential effects

The effects of perinatal exposure to low, intermediate, or highly polluted eels on neonatal, postnatal, adult and middle-aged brain inflammation, and on cognitive performances of middle-aged offspring mice were compared to those of offspring controls. Inflammatory markers in microglia were assessed in offspring on the postnatal days–PNDs 1, 21, 100 and 330. Activated p38MAPK, ERK-1/2 and p65, and acetylcholine levels were assessed in the middle-aged hippocampus. Plasma myeloperoxidase and corticosterone levels were evaluated at PND 330. Learning and its retention, and working memory in middle-aged offspring were assessed using the Morris water maze, and Y-maze. Our results showed enhanced microglia production of inflammatory markers across the lifespan of male as well as female exposed offspring. Inflammation and increased p38 MAPK activation were detected in the exposed middle-aged hippocampus of both exposed sexes. Significant levels of MPO, but not corticosterone, were found in middle-aged males and females perinatally exposed to eels. However, decreases in ERK1/2 and p65 activation, and acetylcholine levels were only detected in female hippocampus exposed to either intermediately or highly polluted eels. Sex selective effects were also detected with regard to memory, the only altered cognitive function. Thus, middle-aged females, but not males, perinatally exposed to either intermediately or highly polluted eels take longer to locate the escape platform, spend considerably less time in the platform and perform less visit to the platform in the retention test. Our results suggest perinatal programming of hippocampal-dependent memory deficit by inflammation in middle-aged offspring, in sex and dose dependent manner.

Does age matter? A mixed methods study examining determinants of good recovery and resilience in young and middle-aged adults following moderate-to-severe traumatic brain injury.

To examine whether age contributes to functional recovery and resilience after moderate-to-severe traumatic brain injury. The ability to recover may change across the lifespan, but the influence of age on brain injury outcome is understudied. Mixed methods study. All adults of working age (18-64years) discharged from a level I trauma centre between 2010-2013 after sustaining a moderate-to-severe traumatic brain injury were considered. Functional recovery was assessed during a telephone interview with the Glasgow Outcome Scale-Extended 12-36months postinjury. A subgroup completed the Connor-Davidson Resilience Scale and a face-to-face interview about resilience. Ninety-seven young (mean age: 27years; 75% male) and 47 middle-aged brain trauma survivors (mean age: 53years; 75% male) completed the telephone interview. Eight young and five middle-aged adults were also assessed for resilience. Overall, young participants experienced more severe head injuries. Yet, they achieved slightly higher levels of functional recovery compared with middle-aged ones as per the Glasgow Outcome Scale-Extended. Controlling for CT scan findings and posttraumatic amnesia duration, age was not found to be associated to functional recovery in adults of working age. Although both groups showed similar levels of resilience, young participants discussed the challenges related to "having more time on their hands" and "being a changed person", two elements perceived positively by middle-aged ones. While age does not appear to interfere with functional recovery in adults of working age, younger brain trauma survivors could benefit from nursing interventions to strengthen their resilience process related to re-employment orientation and identity.

Cortical Surface Thickness in the Middle-Aged Brain with White Matter Hyperintense Lesions.

Background and purpose: Previous voxel-based morphometry (VBM) studies have suggested that cortical atrophy is regionally distributed in middle-aged subjects with white matter hyperintense (WMH) lesions. However, few studies have assessed cortical thickness in middle-aged WMH subjects. In this study, we examined cortical thickness as well as cortical morphometry associated with the presence of WMH lesion load in middle-aged subjects.Participants and methods: Thirty-six middle-aged subjects with WMH lesions (WMH group) and without clinical cognitive impairment, and 34 demographically matched healthy control subjects (HCS group) participated in the study. Cortical thickness was estimated using an automated Computational Anatomy Toolbox (CAT12) as the distance between the gray-white matter border and the pial surface. Individual WMH lesions were manually segmented, and WMH loads were measured. Statistical cortical maps were created to estimate differences in cortical thickness between groups based on this cortex-wide analysis. The relationship between WMH lesion loads and cerebral cortical thickness was also analyzed in CAT12.Results: Cortical thickness was significantly lower in the WMH group than in the controls in multimodal integration regions, including the right and left dorsal anterior cingulate cortex (dACC), right and left frontal operculum (fO), right and left operculum parietale (OP), right and left middle temporal gyrus (MTG), and left superior temporal gyrus (STG; P < 0.01, family-wise error (FWE)-corrected). Additionally, cortical thickness was also lower in the recognition regions that contained the right temporal pole (TP), the right and left fusiform gyrus, and the left rolandic operculum (RO; P < 0.01, FWE-corrected). The results revealed that in the left superior parietal lobule (SPL), cortical thickness was higher in the WMH group than in the HCS group (P < 0.01, FWE-corrected). A voxel-wise negative correlation was found between cortical thickness and WMH lesion loads in the right orbitofrontal cortex (OFC), right dorsolateral prefrontal cortex (DLPFC), and right subcallosal cortex (P < 0.01, FWE-corrected).Conclusion: The main findings of this study suggest that middle-aged WMH subjects are more likely to exhibit cortical thinning, especially in multimodal integration and recognition- and motor-related regions. The current morphometry data provide further evidence for WMH-associated structural plasticity.

Proteins Involved in Endocytosis Are Upregulated by Ageing in the Normal Human Brain: Implications for the Development of Alzheimer's Disease.

The greatest risk factor for Alzheimer's disease (AD) is advanced age, but the reason for this association remains unclear. Amyloid-β (Aβ) is produced from amyloid precursor protein (APP) primarily after APP is internalized by clathrin-mediated or clathrin-independent endocytosis. Changes in endocytosis in AD have been identified. We hypothesized that endocytic protein expression is altered during ageing, thus influencing the likelihood of developing AD by increasing Aβ production. We explored how levels of endocytic proteins, APP, its metabolites, secretase enzymes, and tau varied with age in cortical brain samples from men of three age ranges (young [20-30], middle aged [45-55], and old [70-90]) with no symptoms of dementia. Aβ40 and Aβ42 were significantly increased in old brains, while APP and secretase expression was unaffected by age. Phosphorylated GSK3β increased significantly with age, a possible precursor for neurofibrillary tangle production, although phosphorylated tau was undetectable. Significant increases in clathrin, dynamin-1, AP180, Rab-5, caveolin-2, and flotillin-2 were seen in old brains. Rab-5 also increased in middle-aged brains prior to changes in Aβ levels. This age-related increase in endocytic protein expression, not described previously, suggests an age-related upregulation of endocytosis which could predispose older individuals to develop AD by increasing APP internalization and Aβ generation.

Genome instability: A conserved mechanism of aging?

Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G-CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF + BM-MSC or G-CSF + BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains. Conclusion: While the middle aged brain does not seem to impair drug and cell therapies, in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.

Hypertension-induced impairment in synaptic plasticity and dysregulation of genes involved in synaptic function in the mouse hippocampus: Implications for the pathogenesis of vascular cognitive impairment in aging

Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G-CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF + BM-MSC or G-CSF + BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains. Conclusion: While the middle aged brain does not seem to impair drug and cell therapies, in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.

Stem cell therapies in preclinical models of stroke. Is the aged brain microenvironment refractory to cell therapy?

Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G-CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF+BM-MSC or G-CSF+BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains. Conclusion: While the middle aged brain does not seem to impair drug and cell therapies, in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.

Mitochondrial proteomic profiling reveals increased carbonic anhydrase II in aging and neurodegeneration.

Carbonic anhydrase inhibitors are used to treat glaucoma and cancers. Carbonic anhydrases perform a crucial role in the conversion of carbon dioxide and water into bicarbonate and protons. However, there is little information about carbonic anhydrase isoforms during the process of ageing. Mitochondrial dysfunction is implicit in ageing brain and muscle. We have interrogated isolated mitochondrial fractions from young adult and middle aged mouse brain and skeletal muscle. We find an increase of tissue specific carbonic anhydrases in mitochondria from middle-aged brain and skeletal muscle. Mitochondrial carbonic anhydrase II was measured in the Purkinje cell degeneration (pcd5J) mouse model. In pcd5J we find mitochondrial carbonic anhydrase II is also elevated in brain from young adults undergoing a process of neurodegeneration. We show C.elegans exposed to carbonic anhydrase II have a dose related shorter lifespan suggesting that high CAII levels are in themselves life limiting. We show for the first time that the mitochondrial content of brain and skeletal tissue are exposed to significantly higher levels of active carbonic anhydrases as early as in middle-age. Carbonic anhydrases associated with mitochondria could be targeted to specifically modulate age related impairments and disease.

Density abnormalities in normal-appearing gray matter in the middle-aged brain with white matter hyperintense lesions: a DARTEL-enhanced voxel-based morphometry study.

Background and purposeLittle is known about the structural alterations within gray matter (GM) in middle-aged subjects with white matter hyperintense (WMH) lesions. Here, we aimed to examine the anatomical changes within the GM and their relationship to WMH lesion loads in middle-aged subjects.Participants and methodsTwenty-three middle-aged subjects with WMH lesions (WMH group) and 23 demographically matched healthy control subjects participated in the study. A Diffeomorphic Anatomical Registration Through Exponentiated Liealgebra-enhanced voxel-based morphometry was used to measure the GM density, and the correlations between WMH lesion volume and extracted GM values in abnormal regions were identified by voxel-based morphometry analysis.ResultsCompared with the healthy control subjects, the WMH group had a significantly decreased GM density in the left middle frontal gyrus, bilateral anterior cingulate cortex, left and right premotor cortex, and left and right middle cingulate cortex and an increased GM density in the bilateral cerebellum anterior lobe, left middle temporal gyrus, right temporoparietal junction, left and right prefrontal cortex (PFC), and left inferior parietal lobule. A relationship was observed between the normalized WMH lesion volume and the decreased GM density, including the left middle frontal gyrus (ρ=−0.629, P=0.002), bilateral anterior cingulate cortex (ρ=−0.507, P=0.019), right middle cingulate cortex (ρ=−0.484, P=0.026), and right premotor cortex (ρ=−0.438, P=0.047). The WMH lesion loads also negatively correlated with increased GM density in the right temporoparietal junction (ρ=−0.484, P=0.026), left PFC (ρ=−0.469, P=0.032), and right PFC (ρ=−0.438, P=0.047).ConclusionWe observed that lesion load-associated structural plasticity corresponds to bidirectional changes in regional GM density in the WMH group.

Adenosine A1 Receptor-Mediated Endocytosis of AMPA Receptors Contributes to Impairments in Long-Term Potentiation (LTP) in the Middle-Aged Rat Hippocampus

Aging causes multiple changes in the mammalian brain, including changes in synaptic signaling. Previous reports have shown increased extracellular adenosine in the aging brain, and we recently reported that activation of adenosine A1 receptors (A1Rs) induces AMPA receptor (AMPAR) internalization in rat hippocampus. This study investigated whether aging-related changes in the rat hippocampus include altered surface expression of adenosine A1 and A2A receptors, and whether these changes correspond to changes in AMPAR surface expression and altered synaptic plasticity. We found reduced A1R surface expression in middle-aged rat hippocampus, and also reduced GluA1 and GluA2 AMPAR subunit surface expression. Using a chemically-induced LTP (cLTP) experimental protocol, we recorded fEPSPs in young (1month old) and middle-aged (7-12month old) rat hippocampal slices. There were significant impairments in cLTP in middle-aged slices, suggesting impaired synaptic plasticity. Since we previously showed that the A1R agonist N(6)-cyclopentyladenosine (CPA) reduced both A1Rs and GluA2/GluA1 AMPARs, we hypothesized that the observed impaired synaptic plasticity in middle-aged brains is regulated by A1R-mediated AMPAR internalization by clathrin-mediated endocytosis. Following cLTP, we found a significant increase in GluA1 and GluA2 surface expression in young rats, which was blunted in middle-aged brains or in young brains pretreated with CPA. Blocking A1Rs with 8-cyclopentyl-1,3-dipropylxanthine or AMPAR endocytosis with either Tat-GluA2-3Y peptide or dynasore (dynamin inhibitor) similarly enhanced AMPAR surface expression following cLTP. These data suggest that age-dependent alteration in adenosine receptor expression contributes to increased AMPAR endocytosis and impaired synaptic plasticity in aged brains.