Inflammation as a central mechanism in Alzheimer's disease Kinney, Jefferson W.; Bemiller, Shane M.; Murtishaw, Andrew S. ...
Alzheimer's & dementia : translational research & clinical interventions,
2018, Letnik:
4, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary ...tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive decline of memory and cognitive function. The disease is characterized by the presence of amyloid plaques, ...tau tangles, altered inflammatory signaling, and alterations in numerous neurotransmitter signaling systems, including γ-aminobutyric acid (GABA). Given the extensive role of GABA in regulating neuronal activity, a careful investigation of GABA-related changes is needed. Further, given persistent inflammation has been demonstrated to drive AD pathology, the presence of GABA B receptor expressed on glia that serve a role regulation of the immune response adds to potential implications of altered GABA in AD. There has not previously been a systematic evaluation of GABA-related changes in an amyloid model of AD that specifically focuses on examining changes in GABA B receptors. In the present study, we examined alterations in several GABA-specific targets in the APP/PS1 mouse model at different ages. In the 4-month-old cohort, no significant deficits in spatial learning and memory or alterations in any of the GABAergic targets were observed compared with wild-type controls. However, we identified significant alterations in several GABA-related targets in the 6-month-old cohort that exhibited spatial learning deficits that include changes in glutamic acid decarboxylase 65, GABA transporter type 3, and GABA B receptors protein and mRNA levels. This was the same cohort at which learning and memory deficits and significant amyloid pathology was observed. Overall, our study provides evidence of altered GABAergic signaling in an amyloid model of AD at a time point consistent with AD-related deficits.
•Amyloid pathology in the APP/PS1 mouse models results in changes in proteins associated with GABA synthesis and transport (GAD-65 and GAT3).•APP/PS1 mice exhibit reductions in total protein and mRNA for all 3 subunits of the GABAB receptor in the hippocampus.•Given the data indicating significant changes in GABAB due to amyloid pathology and that GABAB is expressed on neurons and glia the findings in the present study represent a novel mechanism altered in Alzheimer's disease that impacts neuronal and glial function.
•Ketamine SC at 8mg/kg impaired spatial learning consistent with previous findings.•Ketamine induced a significant increase in the number of PV+ neurons in CA3 field of hippocampus.•Ketamine induced ...a significant increase in PV+ neurons outside the SO of the hippocampus.
The underlying mechanisms of schizophrenia pathogenesis are not well understood. Increasing evidence supports the glutamatergic hypothesis that posits a hypofunction of the N-methyl d-aspartate (NMDA) receptor on specific gamma amino-butyric acid (GABA)-ergic neurons may be responsible for the disorder. Alterations in the GABAergic system have been observed in schizophrenia, most notably a change in the expression of parvalbumin (PV) in the cortex and hippocampus. Several reports also suggest abnormal neuronal migration may play a role in the etiology of schizophrenia. The current study examined the positioning and distribution of PV-positive cells in the hippocampus following chronic treatment with the NMDA receptor antagonist ketamine. A robust increase was found in the number of PV-positive interneurons located outside the stratum oriens (SO), the layer where most of these cells are normally localized, as well as an overall numerical increase in CA3 PV cells. These results suggest ketamine leads to an abnormal distribution of PV-positive cells, which may be indicative of aberrant migratory activity and possibly related to the Morris water maze deficits observed. These findings may also be relevant to alterations observed in schizophrenia populations.
The feasibility, safety, and efficacy of a high-intensity multimodal exercise program (aerobic, strengthening, and balance training) have not been well vetted in persons with Parkinson disease (PD). ...Thus, the primary aim was to determine whether a high-intensity multimodal exercise boot camp (HIBC) was both feasible and safe in persons with PD. The secondary aim was to determine whether the program would produce greater benefit than a usual care, low-intensity exercise program (UC). An exploratory aim was to determine whether these programs affected putative disease-modifying mechanisms.
Twenty-seven participants (19 men and 8 women) were randomized into 8 weeks of either the HIBC or UC supervised by physical therapists. For feasibility, participation, and meeting, Centers for Disease Control and Prevention (CDC) exercise guidelines were assessed. For safety, adverse events were monitored. For efficacy, the following outcome domains were assessed before and after participation: balance, motor activity, endurance and fatigue, strength, mental health, and quality of life. For disease-modifying mechanisms, circulating brain-derived neurotrophic factor (BDNF) and its genotype, superoxide dismutase, and cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-10) were monitored.
The HIBC was better at attaining CDC guidelines (P = 0.013) and spent more minutes in higher-intensity exercise per week (P < 0.001). There were no differences in adverse events (P = 0.419). The HIBC experienced significant improvements in 7/31 outcomes versus 3/31 in the UC arm. BDNF improved significantly for both groups from pre- to posttests (Ps ≤ 0.041) and an improved anti-inflammatory was observed for both groups.
A high-intensity multimodal exercise boot camp was feasible and safe in persons with PD. Compared with usual care, there were no differences in adverse events. Moreover, the high-intensity multimodal exercise program produced more improvement across more domains than usual care. Our results also suggest a possible link between improvement in outcomes and an improved anti-inflammatory milieu.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A244).
Diabetes mellitus (DM) is a major risk factor for Alzheimer's disease and vascular dementia. Few animal models exist that focus on the metabolic contributions to dementia onset and progression. Thus, ...there is strong scientific rationale to explore the effects of streptozotocin (STZ), a diabetogenic compound, on vascular and inflammatory changes within the brain.
The present study was designed to evaluate the effect of staggered, low-dose administration of STZ on behavioral and cognitive deficits, neuroinflammation, tau pathology, and histopathological alterations related to dementia.
Staggered administration (Days 1, 2, 3, 14, 15) of streptozotocin (40 mg/kg/mL) induced a diabetic-like state in mice, resulting in sustained hyperglycemia. STZ-treated animals displayed memory deficits in the novel object recognition task as well as increased tau phosphorylation and increased neuroinflammation. Additionally, STZ led to altered insulin signaling, exhibited by decreased plasma insulin and decreased levels of insulin degrading enzyme and pAKT within the hippocampus.
STZ-treated animals exhibit cognitive deficits and histopathological changes seen in dementia. This model of dementia warrants continued investigation to better understand the role that DM plays in dementia-related alterations.
•Intermittent peripheral streptozotocin induced a sustained hyperglycemic state in an otherwise completely healthy animal.•Sustained hyperglycemia resulted in increased inflammatory signaling as well as elevated ptau and learning and memory deficits.•The hyperglycemia also induced alterations in insulin and insulin signaling mechanisms, as well as evidence of microvascular hemorrhages.
Mammalian hibernation in ground squirrels is characterized by periods of torpor wherein body temperature approaches ambient temperature and metabolism is reduced to as low as 1/100th of active rates. ...It is unclear how hibernation affects long-term spatial memory, as tremendous remodeling of neurons is associated with torpor use. Given the suspected links between remodeling and memory formation and retention, we examined long-term spatial memory retention throughout a hibernation season. Animals were trained on a Barnes maze before entering torpor. Animals were tested for memory retention once a month throughout a hibernation season. Results indicate marked variation between individuals. Some squirrels retained memory across multiple torpor bouts, while other squirrels did not. No relationship was found between the number of torpor bouts, duration of bouts, or time spent torpid on long-term memory retention. However, that some squirrels successfully retain memory suggests that the profound remodeling of dendritic spines during torpor does not always lead to memory loss.
Lipopolysaccharide (LPS) is often used to investigate the exacerbatory effects of an immune-related challenge in transgenic models of various neurodegenerative diseases. However, the effects of this ...inflammatory challenge in an insulin resistant brain state, as seen in diabetes mellitus, a major risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), is not as well characterized. We investigated the effects of an LPS-induced inflammatory challenge on behavioral and biological parameters following intracerebroventricular (ICV) injection of streptozotocin (STZ) in male Sprague–Dawley rats. Subjects received a one-time bilateral ICV infusion of STZ (25 mg/mL, 8 μL per ventricle) or ACSF. One week following ICV infusions, LPS (1 mg/mL, i.p.) or saline was administered to activate the immune system. Behavioral testing began on the 22nd day following STZ-ICV infusion, utilizing the open field and Morris water maze (MWM) tasks. Proteins related to immune function, learning and memory, synaptic plasticity, and key histopathological markers observed in VaD and AD were evaluated. The addition of an LPS-induced immune challenge partially attenuated spatial learning and memory deficits in the MWM in STZ-ICV injected animals. Additionally, LPS administration to STZ-treated animals partially mitigated alterations observed in several protein levels in STZ-ICV alone, including NR2A, GABAB1, and β-amyloid oligomers. These results suggest that an acute LPS-inflammatory response has a modest protective effect against some of the spatial learning and memory deficits and protein alterations associated with STZ-ICV induction of an insulin resistant brain state.
•An inflammatory challenge was administered in STZ-ICV animals.•STZ impaired spatial memory (MWM) and altered brain protein expression.•The addition of LPS (STZ/LPS) conferred a modest protection in the MWM.•STZ/LPS prevented alterations in several brain proteins.•Acute inflammation may play beneficial role in preventing early AD-like symptoms.
► Subanesthetic administration of ketamine produced deficits in trace cued fear. ► Ketamine produced no significant deficits in delay cued fear or contextual fear. ► Ketamine also impaired ...sensorimotor gating consistent with models of schizophrenia. ► Data indicate subanesthetic ketamine produces a disruption of specific circuits.
Alterations in N-methyl-d-aspartate (NMDA) receptor function have been linked to numerous behavioral deficits and neurochemical alterations. Recent investigations have begun to explore the role of NMDA receptor function on principally inhibitory neurons and their role in network function. One of the prevailing models of schizophrenia proposes a reduction in NMDA receptor function on inhibitory interneurons and the resulting disinhibition may give rise to aspects of the disorder. Studies using NMDA receptor antagonists such as PCP and ketamine have induced schizophrenia-like behavioral deficits in animal model systems as well as changes in inhibitory circuits. The current study investigated whether the administration of a subanesthetic dose of ketamine (8mg/kg subcutaneously), that disrupts sensorimotor gating, also produces impairments in a Pavlovian emotional learning and memory task. We utilized both standard delay and trace cued and contextual fear conditioning (CCF) paradigms to examine if ketamine produces differential effects when the task is more difficult and relies on connectivity between specific brain regions. Rats administered ketamine displayed no significant deficits in cued or contextual fear following the delay conditioning protocol. However, ketamine did produce a significant impairment in the more difficult trace conditioning protocol. Analyses of tissue from the hippocampus and amygdala indicated that the administration of ketamine produced an alteration in GABA receptor protein levels differentially depending on the task. These data indicate that 8mg/kg of ketamine impairs learning in the more difficult emotional classical conditioning task and may be related to altered signaling in GABAergic systems.
•GABAB agonist or antagonist on PND 7, 9, and 12 produced PPI deficits in adulthood.•Proteins associated with GABA signaling and plasticity were altered in adulthood.•Differences in the effects of ...the GABAB ligands were observed between genders.
The GABA transmitter system plays a vital role in modulating synaptic formation and activity during development. The GABAB receptor subtype in particular has been implicated in cell migration, promotion of neuronal differentiation, neurite outgrowth, and synapse formation but it's role in development is not well characterized. In order to investigate the effects of brief alterations in GABAB signaling in development, we administered to rats the GABAB agonist baclofen (2.0mg/kg) or antagonist phaclofen (0.3mg/kg) on postnatal days 7, 9, and 12, and evaluated sensorimotor gating in adulthood. We also examined tissue for changes in multiple proteins associated with GABAB receptor function and proteins associated with synapse formation. Our data indicate that early postnatal alterations to GABAB receptor-mediated signaling produced sex differences in sensorimotor gating in adulthood. Additionally, we found differences in GABAB receptor subunits and kalirin protein levels in the brain versus saline treated controls. Our data demonstrate that a subtle alteration in GABAB receptor function in early postnatal life induces changes that persist into adulthood.
PDF
