Astrogliosis and episodic memory in late life: higher GFAP is related to worse memory and white matter microstructure in healthy aging and Alzheimer's disease.

Astrocytes play a formative role in memory consolidation during physiological conditions; when dysregulated, astrocytes release glial fibrillary acidic protein (GFAP), which has been linked with negative memory outcomes in animal studies. We examined the association between blood GFAP, memory, and white matter (WM) integrity, accounting for blood markers of AD pathology (i.e., Aß42) and neurodegeneration (i.e., total tau; neurofilament light chain) in 114 older adults (asymptomatic, n = 69; MCI/AD dementia, n = 45). Higher levels of GFAP were associated with lower memory scores (p < 0.0001), such that for 1 SD increase in mean GFAP values, the memory composite score decreased on average by 0.49 (Standard error = 0.071). These results remained significant after controlling for diagnostic status and AD-related blood biomarkers. Higher GFAP was also related to lower WM integrity in regions vulnerable to AD pathology; however, WM integrity did not account for the association between GFAP and memory. Study findings suggest that higher blood levels of a marker of astrogliosis may reflect impoverished memory functions and white matter health, independent of markers of amyloid or neurodegeneration.

Tooth Loss Induces Memory Impairment and Gliosis in App Knock-In Mouse Models of Alzheimer's Disease.

BACKGROUND: Epidemiological studies have shown that tooth loss is associated with Alzheimer's disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. OBJECTIVE: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in AppNL-G-F mice. METHODS: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL-G-F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-ß (Aß) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aß ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. RESULTS: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. CONCLUSION: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.

Investigation of reactive astrogliosis effect on post-stroke cognitive impairment.

BACKGROUND: The aim of this study is to investigate the associations between post-stroke cognitive impairment (PSCI) severity and reactive astrogliosis (RA) extent on normalized 18F-THK-5351 positron-emission tomography (PET) imaging in amyloid-negative patients with first-ever stroke. METHODS: We prospectively enrolled 63 amyloid-negative patients with first-ever stroke. Neurocognitive evaluation, MRI, 18F-THK-5351, and 18F-florbetapir PET were performed around 3 months after stroke. The 18F-THK-5351 uptake intensity was normalized using a signal distribution template to obtain the Z-SUM scores as the RA extent in the whole brain and cerebral hemisphere ipsilateral to stroke lesion. We evaluated stroke volume, leukoaraiosis, and brain atrophy on MRI. We used a comprehensive neurocognitive battery to obtain composite cognitive scores, and defined PSCI as a general cognitive function score < - 1. We analyzed the influence of Z-SUM scores on PSCI severity after adjusting for demographic, vascular, and neurodegenerative variables. RESULTS: Twenty-five of 63 stroke patients had PSCI. Patients with PSCI had older age, lower education, and more severe cortical atrophy and total Z-SUM scores. Total Z-SUM scores were significantly associated with general cognitive and executive functions at multiple regression models. Path analyses showed that stroke can exert cognitive influence directly by stroke itself as well as indirectly through RA, including total and ipsilateral Z-SUM scores, in patients with either right or left hemisphere stroke. CONCLUSION: The patterns and intensity of 18F-THK-5351 uptake in amyloid-negative patients with first-ever stroke were associated with PSCI manifestations, which suggests that RA presents a modulating effect in PSCI development.

Microgliosis is associated with visual memory decline in patients with temporal lobe epilepsy and hippocampal sclerosis: A clinicopathologic study.

Hippocampal sclerosis (HS) is characterized by neuronal loss and gliosis. The intensity and distribution of these histopathological findings over the Cornu Ammonis (CA) subfields are important for the classification of HS and prognostication of patients with temporal lobe epilepsy (TLE). Several studies have associated the neuronal density reduction in the hippocampus with cognitive decline in patients with TLE. The current study aimed at investigating whether the expression of glial proteins in sclerotic hippocampi is associated with presurgical memory performance of patients with TLE. Before amygdalohippocampectomy, patients were submitted to memory tests. Immunohistochemical and morphometric analyses with glial fibrillary acidic protein (GFAP) for astrogliosis and human leucocyte antigen DR (HLA-DR) for microgliosis were performed in paraffin-embedded HS and control hippocampi. Sclerotic hippocampi exhibited increased gliosis in comparison with controls. In patients with TLE, the area and intensity of staining for HLA-DR were associated with worse performance in the memory tests. Glial fibrillary acidic protein was neither associated nor correlated with memory test performance. Our data suggest association between microgliosis, but not astrogliosis, with visual memory decline in patients with TLE.

Amyloid-ß plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease.

BACKGROUND: Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce Aß without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of AD. Previously, we reported that AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. To determine whether these mice exhibit deficits in learning and memory at more advanced ages, we compared the Morris water maze performance of AppNL-G-F and AppNL mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months. To correlate cognitive deficits and neuroinflammation, we also examined Aß plaque formation and reactive gliosis in these mice. RESULTS: In the Morris water maze, a spatial task, 24-month-old AppNL-G-F/NL-G-F mice exhibited significantly poorer spatial learning than WT mice during the hidden training sessions, but similarly to WT mice during the visible training sessions. Not surprisingly, AppNL-G-F/NL-G-F mice also exhibited spatial memory deficits both 1 and 7 days after the last training session. By contrast, 24-month-old AppNL/NL mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that 24-month-old AppNL-G-F/NL-G-F mice developed massive Aß plaques and reactive gliosis (microgliosis and astrocytosis) throughout the brain, including the cortex and hippocampus. By contrast, we observed no detectable brain pathology in AppNL/NL mice despite overproduction of human Aß40 and Aß42 in their brains. CONCLUSIONS: Aß plaque formation, followed by sustained neuroinflammation, is necessary for the induction of definitive cognitive deficits in App-KI mouse models of AD. Our data also indicate that introduction of the Swedish mutation alone in endogenous APP is not sufficient to produce either AD-related brain pathology or cognitive deficits in mice.

The Time Course of Recognition Memory Impairment and Glial Pathology in the hAPP-J20 Mouse Model of Alzheimer's Disease.

The role of cellular changes in the neurovascular unit is increasingly being investigated to understand the pathogenesis of Alzheimer's disease (AD). The aim of the current study was to determine the time course of recognition memory impairment in the J20 mouse model of AD, in relation to neuroinflammatory responses and the pathology of amyloid-ß (Aß). Male hAPP-J20 and wild-type mice were assessed at 3, 6, 9, and 12 months of age. The spontaneous object recognition (SOR) task provided a measure of memory, with assessment of both a short delay (1 min) and a long delay (4 h). Immunohistochemistry was used to characterize Aß deposition, and quantify astrocyte and microglial responses. At all ages tested, J20 mice had impaired long-term, but preserved short-term, recognition memory. Wild-types demonstrated preserved long-term memory up to 9 months of age, and preserved short-term memory at all ages tested. Plaque pathology in the J20 mice was present from 6 months onwards, with co-localization of reactive microglia and activated astrocytes. Reactive microglia and astrocyte activation in the hippocampus were significantly greater in the J20 mice at 9 months, compared to wild-types. This study contributes to our understanding of the pathological and cognitive mechanisms at play in AD. J20 mice showed impairment in retaining information over longer periods from an early age, preceding the deposition of Aß and glial activation. Defining early physiological changes in relation to cognitive decline could provide insight into new therapeutic targets early in the disease process, when intervention is most likely to effectively slow disease progression.

Repeated mild traumatic brain injury produces neuroinflammation, anxiety-like behaviour and impaired spatial memory in mice.

PRIMARY OBJECTIVE: Repeated traumatic brain injuries (rmTBI) are frequently associated with debilitating neuropsychiatric conditions such as cognitive impairment, mood disorders, and post-traumatic stress disorder. We tested the hypothesis that repeated mild traumatic brain injury impairs spatial memory and enhances anxiety-like behaviour. RESEARCH DESIGN: We used a between groups design using single (smTBI) or repeated (rmTBI) controlled cranial closed skull impacts to mice, compared to a control group. METHODS AND PROCEDURES: We assessed the effects of smTBI and rmTBI using measures of motor performance (Rotarod Test [RT]), anxiety-like behaviour (Elevated Plus Maze [EPM] and Open Field [OF] tests), and spatial memory (Morris Water Maze [MWM]) within 12 days of the final injury. In separate groups of mice, astrocytosis and microglial activation were assessed 24 hours after the final injury using GFAP and IBA-1 immunohistochemistry. MAIN OUTCOMES AND RESULTS: RmTBI impaired spatial memory in the MWM and increased anxiety-like behaviour in the EPM and OFT. In addition, rmTBI elevated GFAP and IBA-1 immunohistochemistry throughout the mouse brain. RmTBI produced astrocytosis and microglial activation, and elicited impaired spatial memory and anxiety-like behaviour. CONCLUSIONS: rmTBI produces acute cognitive and anxiety-like disturbances associated with inflammatory changes in brain regions involved in spatial memory and anxiety.

Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia.

Vascular cognitive impairment is the second most common form of dementia. The pathogenic pathways leading to vascular cognitive impairment remain unclear but clinical and experimental data have shown that chronic reactive astrogliosis occurs within white matter lesions, indicating that a sustained pro-inflammatory environment affecting the white matter may contribute towards disease progression. To model vascular cognitive impairment, we induced prolonged mild cerebral hypoperfusion in mice by bilateral common carotid artery stenosis. This chronic hypoperfusion resulted in reactive gliosis of astrocytes and microglia within white matter tracts, demyelination and axonal degeneration, consecutive spatial memory deficits, and loss of white matter integrity, as measured by ultra high-field magnetic resonance diffusion tensor imaging. White matter astrogliosis was accompanied by activation of the pro-inflammatory transcription factor nuclear factor (NF)-kB in reactive astrocytes. Using mice expressing a dominant negative inhibitor of NF-kB under the control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter (GFAP-IkBα-dn), we found that transgenic inhibition of astroglial NF-kB signaling ameliorated gliosis and axonal loss, maintained white matter structural integrity, and preserved memory function. Collectively, our results imply that pro-inflammatory changes in white matter astrocytes may represent an important detrimental component in the pathogenesis of vascular cognitive impairment, and that targeting these pathways may lead to novel therapeutic strategies.

Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype.

A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood. Type-1 interferons (IFNs) are master regulators of innate immunity and have been implicated in multiple CNS disorders, however their role in AD progression has not yet been fully investigated. Hence, we generated APPSWE/PS1ΔE9 mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APPSWE/PS1ΔE9 x IFNAR1(-/-)) aged to 9 months to investigate the role of type-1 IFN signaling in a well-validated model of AD. APPSWE/PS1ΔE9 x IFNAR1(-/-) mice displayed a modest reduction in Aß monomer levels, despite maintenance of plaque deposition. This finding correlated with partial rescue of spatial learning and memory impairments in the Morris water maze in comparison to APPSWE/PS1ΔE9 mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice compared to APPSWE/PS1ΔE9 mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice in comparison to APPSWE/PS1ΔE9 mice. These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aß1-42 treatment of IFNAR1(-/-) primary glial cultures. Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD.

T2 relaxation time alterations underlying neurocognitive deficits in alcohol-use disorders (AUD) in an Indian population: A combined conventional ROI and voxel-based relaxometry analysis.

Long-term heavy alcohol consumption has traditionally been associated with impaired cognitive abilities, such as deficits in abstract reasoning, problem solving, verbal fluency, memory, attention, and visuospatial processing. The present study aimed at exploring these neuropsychological deficits in alcohol-use disorders (AUD) in an Indian population using the Postgraduate Institute Battery of Brain Dysfunction (PGIBBD) and their possible correlation with alterations in T2 relaxation times (T2-RT), using whole-brain voxel-based relaxometry (VBR) and conventional region of interest (ROI) approach. Multi-echo T2 mapping sequence was performed on 25 subjects with AUD and 25 healthy controls matched for age, education, and socioeconomic status. Whole-brain T2-RT measurements were conducted using VBR and conventional ROI approach. The study was carried out on a 3T whole-body MR scanner. Post processing for VBR and ROI analysis was performed using SPM 8 software and vendor-provided software, respectively. A PGIBBD test battery was conducted on all subjects to assess their cognitive abilities, and the results were reported as raw scores. VBR and ROI results revealed that AUD subjects showed prolonged T2-RTs in cerebellum bilaterally, parahippocampal gyrus bilaterally, right anterior cingulate cortex, left superior temporal gyrus, left middle frontal gyrus, and left calcarine gyrus. A significant correlation was also observed between the neuropsychological test raw scores and alterations in T2-RT in AUD subjects. Our results are consistent with previous studies suggesting tissue disruption or gliosis or demyelination as a possible reason for prolonged T2-RTs. This damage to brain tissue, which is evident as prolonged T2-RT, could possibly be associated with impaired cognitive abilities noticeable in AUD subjects.

Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats.

Connexin43 (Cx43) is one of the most abundant gap junction proteins in the central nervous system. Abnormal opening of Cx43 hemichannels after ischemic insults causes apoptotic cell death. In this study, we found persistently increased expression of Cx43 8 h to 7 d after hypoxia/ischemia (HI) injury in neonatal rats. Pre-treatment with Gap26 and Gap27, two Cx43 mimetic peptides, significantly reduced cerebral infarct volume. Gap26 treatment at 24 h after ischemia improved functional recovery on muscle strength, motor coordination, and spatial memory abilities. Further, Gap26 inhibited Cx43 expression and reduced active astrogliosis. Gap26 interacted and co-localized with Cx43 together in brain tissues and cultured astrocytes. After oxygen glucose deprivation, Gap26 treatment reduced the total Cx43 level in cultured astrocytes; but Cx43 level in the plasma membrane was increased. Degradation of Cx43 in the cytoplasm was mainly via the ubiquitin proteasome pathway. Concurrently, phosphorylated Akt, which phosphorylates Cx43 on Serine(373) and facilitates the forward transport of Cx43 to the plasma membrane, was increased by Gap26 treatment. Microdialysis showed that increased membranous Cx43 causes glutamate release by opening Cx43 hemichannels. Extracellular glutamate concentration was significantly decreased by Gap26 treatment in vivo. Finally, we found that cleaved caspase-3, an apoptosis marker, was attenuated after HI injury by Gap26 treatment. Effects of Gap27 were analogous to those of Gap26. In summary, our findings demonstrate that modulation of Cx43 expression and astroglial function is a potential therapeutic strategy for ischemic brain injury.

Astrogliosis and behavioral changes in mice lacking the neutral cysteine protease bleomycin hydrolase.

Bleomycin hydrolase (BLMH) is a multifaceted neutral cysteine protease with a suggested role in antigen presentation, homocysteine-thiolactone metabolism, and Alzheimer's disease pathogenesis. Deletion of the protease in mice results in increased neonatal mortality and dermatopathology. Immunohistochemical and behavioral studies of BLMH knockout mice were undertaken to further evaluate the role of the protease in the brain. No gross abnormalities in the CNS were observed upon preliminary histological examination of B6.129Blmhtm1Geh/J null animals. However, glial fibrillary acid protein immunohistochemistry revealed a global reactive astrogliosis in the aged null animals, indicative of undefined brain pathology. The role of BLMH in the brain was further explored by characterizing the behavioral phenotype of hybrid [129S6-Blmhtm1Geh/JxB6.129 Blmhtm1Geh/J]F1 null and littermate controls using multiple behavioral paradigms. In the water maze, deletion of BLMH resulted in poorer performance during water maze probe trials without detectable effect of the mutation on sensorimotor function. In addition, no age-dependent decline in discriminative performance on probe trials was observed in null animals. These data suggest a physiological non-redundant function for BLMH in the CNS.

Canine cognitive deficit correlates with diffuse plaque maturation and S100beta (-) astrocytosis but not with insulin cerebrospinal fluid level.

Like humans, canines develop with aging beta-amyloid (Abeta) plaques and a progressive cognitive deficit on tasks similar to those used in diagnosis and follow-up of Alzheimer's disease. Owing to that, dogs are quite unique to investigate the early events taking place in the diffuse Abeta plaque maturation and its relationship with cognitive deficit. The aim of the present investigation was to study the link between the diffuse Abeta plaque maturation and the astro- and microglial reactivity. The involvement of insulin and beta-subunit of S100 protein (S100beta) overexpression in the process was also investigated. Abeta plaques were measured and counted in prefrontal cortex of 16 pet dogs of different breeds, weight and sex, classified as control and with a light or severe cognitive deficit. A correlation between canine graded cognitive deficit, diffuse plaque maturation, and S100beta (-) astrocytosis, but not with cerebrospinal fluid insulin level, was found that may reflect the very early events of Abeta deposition in Alzheimer's disease.

Familial progressive subcortical gliosis.

We report clinical and pathologic findings from two kindreds afflicted with a familial form of progressive subcortical gliosis. The disorder segregated as an autosomal dominant trait. Onset was in the presenium and the course was slowly progressive. Affected individuals initially manifested personality change, degeneration of social ability, disinhibition, psychotic symptoms, memory impairment, or depression. Later, all developed progressive dementia, frequently associated with verbal stereotypy, decreased speech output, echolalia, or manifestations of the human Klüver-Bucy syndrome. Terminal clinical manifestations included profound dementia, frequently with mutism, dysphagia, and extrapyramidal signs. Autopsy of seven end-stage patients revealed generalized cerebral atrophy, predominantly involving the white matter of the frontal and temporal lobes. Microscopically, prominent fibrillary astrocytosis was present in the subcortical white matter and in the subpial and deep layers of the overlying cerebral cortex. These changes were most pronounced in the frontal and temporal lobes, especially in the cingulate gyri and insulae. Mild cortical neuronal loss accompanied the gliosis, but no myelin loss was evident. The claustra and substantia nigra also showed severe astrocytosis and degenerative changes. Amyloid deposits and neuronal cytoskeletal inclusions were absent.

Prefrontal neocortical disturbances in mental retardation.

Morphometrical analysis of the frontal lobe neocortex of seven selected cases of mental retardation of unclassified aetiology and pathology, showing mild dysplastic changes of the neocortex on routine workup, were compared with nine normal controls and seven cases with Down's syndrome. In comparison with the normal controls, the group with 'unclassified' mental retardation showed an increased percentage of disoriented pyramidal neurons in layers III and IV-V (8-17%, P < 0.01), an abnormal distribution of small pyramidal cells with a shift from superficial to deeper layers of the prefrontal cortex (P < 0.01), and an increased cortical thickness (+38%, P < 0.05) of Brodmann area 10, as well as a tendency to a decreased gyration of the frontal lobe sulci (-14%, P = 0.18). However, no statistically significant macroscopical differences either in frontal lobe gyration or in the size of the cerebrum and its frontal lobes were found between these two groups. On the other hand, the Down's syndrome group had a significantly decreased gyration (-36%, P < 0.01). These findings may indicate an inhibited and disordered migration of putative small pyramidal neurons in cases of 'unclassified' mental retardation.