Aging leads to altered microglial function that reduces brain resiliency increasing vulnerability to neurodegenerative diseases

doi:10.1016/j.exger.2017.01.027

Experimental Gerontology

Volume 94, August 2017, Pages 4-8

https://doi.org/10.1016/j.exger.2017.01.027 Get rights and content

Highlights

•
Aging leads to reduced resilience of the brain that underlies neurodegenerative disease prevalence.
•
Altered function of microglia is one source of reduced resilience in the aging brain.
•
Polyphenol rich dietary supplements can increase resilience in the aged brain.

Abstract

Aging is the primary risk factor for many neurodegenerative diseases. Thus, understanding the basic biological changes that take place with aging that lead to the brain being less resilient to disease progression of neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease or insults to the brain such as stroke or traumatic brain injuries. Clearly this will not cure the disease per se, yet increasing the ability of the brain to respond to injury could improve long term outcomes. The focus of this review is examining changes in microglia with age and possible therapeutic interventions involving the use of polyphenol rich dietary supplements.

Section snippets

Microglial changes with age

Microglia are continually assessing the microenvironment and can respond to a variety of stimuli by rapidly moving between activation states. These activation states were initially termed M1 or classical pro-inflammatory and M2 or alternative activation. There is an ongoing balance of expression of cytokines from microglia depending on the surrounding signaling molecules. However, it is important to mention that it is becoming clear that microglial phenotype is quite complex. Some researchers

Impact of inflammation on neural plasticity

The impacts of the changes in microglial function with age are numerous. There is strong evidence for cell non-autonomous effects on stem cell niches, with much of the evidence for this coming from studies using heterochronic parabiosis wherein the circulation of two animals of different ages is combined and early studies in our lab using the technique of in oculo transplantation. These latter experiments excised embryonic CNS tissues and transplanted the grafts into in the anterior chamber of

Approaches to modulating the systemic milieu and local inflammatory cell influences on the stem cell niche

With the summary of the literature included above, it is established that several cell non autonomous sources have a negative impact on the stem cell niche are present with age. We have examined a number of strategies for modulating the non-autonomous mechanisms. One of the approaches we have used to mitigate these detrimental age-related changes in the CNS is a dietary intervention using polyphenol rich diets. Our group has established that a proprietary combination of natural ingredients

Polyphenol rich diets effects on the system milieu with age

In a recent paper we used an in vitro approach designed to mimic parabiosis, where we examined the effect of serum from young and aged rats on proliferation of MSC and NPC's in culture (Bickford et al., 2015). Furthermore, this study also assessed additional experimental groups that had been treated with a polyphenol rich diet. Serum was collected from both young rats (4 months) and aged rats (21 months) with or without supplementation with NT-020 (135 mg/kg) for one month. NPC's were grown in

Polyphenol rich diets reduce microglial pro-inflammatory activation, increase neurogenesis, and improve learning in aged rats

Polyphenols are potent modulators of inflammation in the aged brain and are thus a potential therapeutic approach to increase the resiliency of the aged brain to insults and improve homeostasis. Work from our lab and others support the role of polyphenols and other components of complex botanical mixtures to increase Nrf2 as a main mechanism of action (Bhullar and Rupasinghe, 2013, Shah et al., 2010, Turan et al., 2012). Data from our lab shows that a NT-020, a polyphenol rich supplement,

Acknowledgements

This work was supported by NIH grants R01AG044919 (PCB), and VA grant I01BX003421 (PCB).

This work was supported by the Veterans Administration (I01BX003421). Content does not represent the views of the Department of Veterans Affairs nor the US Government.

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Dietary Inflammatory Index score and prodromal Parkinson's disease incidence: The HELIAD study
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Application of effective therapeutic interventions at this early stage of neurodegeneration is presented as one of the public health challenges for the decades to come [3,7]. Besides aging, which is one of the primary risk factor for PD [4,8], other factors (genetic, environment and lifestyle) also seem to play an important role in PD progression. In fact, less than 5% of PD cases have well-defined genetic basis, suggesting that environmental and lifestyle factors may be the leading risk factors for developing PD [9].
The aim of the present study was to investigate the association of the inflammatory potential of diet with prodromal Parkinson's disease (pPD) probability and incidence among community-dwelling older individuals without clinical features of parkinsonism at baseline. The sample consisted of 1,030 participants 65 years old or older, drawn from a population-based cohort study of older adults in Greece (Hellenic Longitudinal Investigation of Aging and Diet - HELIAD). We calculated pPD probability, according to International Parkinson and Movement Disorder Society research criteria. Dietary Inflammatory Index (DII) was used to measure the dietary inflammatory potential, with higher index score reflecting a more pro-inflammatory diet. Associations of baseline DII with pPD probability cross-sectionally, and with possible/probable pPD incidence (pPD probability ≥30%) during the follow-up period, were examined via general linear models and generalized estimating equations, respectively. Cross-sectionally, one unit increase of DII score [DII (min, max) = -5.83, 6.01] was associated with 4.9% increased pPD probability [β=0.049, 95%CI (0.025-0.090), p<0.001]. Prospectively, 62 participants developed pPD during 3.1±0.9 (mean±SD) years of follow-up. One unit increase in DII was associated with 20.3% increased risk for developing pPD [RR=1.203, 95%CI (1.070–1.351), p=0.002]. Participants in the highest tertile of DII score were 2.6 times more likely to develop pPD [β=2.594, 95%CI (1.332–5.050), p=0.005], compared to those in the lowest tertile. More pro-inflammatory diet was related with higher pPD probability and pPD incidence (pPD probability ≥30%) in a community-dwelling older adult population. Further studies are needed to confirm these findings.
Effects of repetitive Transcranial Magnetic Stimulation in aged rats depend on pre-treatment cognitive status: Toward individualized intervention for successful cognitive aging
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However, successful aging is also accompanied by a variety of compensatory or adaptive processes, yielding plasticity, circuit dynamics, and cognitive strategies distinct from young. Since aging leads to reduced resilience to insults [75], rTMS may have worked as a perturbation that could not be overcome in cognitively intact animals that received treatment. Our findings suggest that the constellation of neural adaptations that support positive cognitive outcomes also render the aged brain vulnerable to disruption after stimulation, under conditions that have little effect in younger individuals.
Repetitive Transcranial Magnetic Stimulation (rTMS) has shown initial promise in combating age-related cognitive decline and dementia. The nature and severity of cognitive aging, however, varies markedly between individuals.
We hypothesized that the distinct constellation of brain changes responsible for individual differences in cognitive aging might influence the response to rTMS.
Cognitive effects of rTMS were evaluated using a rat model of cognitive aging in which aged rats are classified as Aged-Impaired (AI) or -Unimpaired (AU) relative to young (Y) according to their performance in the Morris water maze. Several weeks later, following presentation of a sample odor in an olfactory recognition task, rats received either sham (Y, n = 9; AU, n = 8; AI, n = 9) or intermittent Theta Burst Stimulation (Y, n = 8; AU, n = 8; AI, n = 9). Memory was tested 24 h later.
Recognition memory in the sham and stimulated conditions depended on pre-treatment cognitive status in the aged rats. Y and AU sham rats displayed robust odor recognition, whereas sham-treated AI rats exhibited no retention. In contrast, rTMS treated AI rats showed robust retention, comparable in magnitude to Y, whereas the AU stimulated scored at chance.
Our results are consistent with a perspective that the unique neurobiology associated with variability in cognitive aging modulates the response to rTMS. Protocols with documented efficacy in young adults may have unexpected outcomes in aging or neurodegenerative conditions, requiring individualized approaches.
Event-related potentials of episodic encoding after traumatic brain injury in older adults
2021, Brain Research
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Moreover, they present more severe cognitive deficits than young adults for a similar TBI severity (Ashman et al., 2008; Marquez de la Plata et al., 2008). Accordingly, there is a growing body of evidence suggesting that the aging brain is less resilient and has a limited capacity to regenerate after a brain injury (Bickford et al., 2017; Irimia et al., 2018; Ziebell et al., 2017). In a study on the long-term impacts (5–22 years) of mild-to-severe TBI, Senathi-Raja et al. (2010) showed that individuals with TBI aged between 16 and 81 years at the time of injury showed impaired performances in tests assessing working memory, episodic memory in both verbal and visuo-spatial modalities, executive functions and processing speed.
Episodic memory and attention impairments are frequently observed following a traumatic brain injury (TBI). Older adults are more affected than young adults after a TBI, partly because of the age-related neural and memory changes. Neural mechanisms underlying episodic memory deficits in older adults with chronic TBI remain to be investigated. The current study aimed to investigate the impact of TBI in older adults on the neural mechanisms of episodic encoding. Event-related potentials were recorded while 13 participants with mild-to-severe TBI and 14 matched controls were performing an episodic memory task in which the level of organizational strategy was manipulated through three encoding conditions. Participants were explicitly instructed to memorize words without any semantic relationship (Unrelated condition), words semantically related without any given strategies (Spontaneous condition) and words semantically related with provided category labels and organizational strategy (Guided condition). Behavioral performances indicated that older individuals with a TBI were impaired compared to matched controls whatever the condition. The electrophysiological findings showed a reduction of the P200 and LPC components amplitude in the TBI group relative to control group. Moreover, control participants without any neurological history showed a right frontal sustained activity only in the Spontaneous condition, whereas a right frontal asymmetry was observed in participants with chronic TBI whatever the encoding conditions. This was mainly the result of negative left frontal activity. These findings evidence neural dysfunctions underlying attentional and associative processes involved in memory strategies after a TBI sustained at an older age that are consistent with executive functions impairments.
Effect of ladostigil treatment of aging rats on gene expression in four brain areas associated with regulation of memory: Selective changes by ladostigil in gene expression in aging brain
2020, Neuropharmacology
Citation Excerpt :
In addition, the aged brain has a decrease in the expression of neurotrophic factors like, BDNF, NGF and IGF-1 that may also impair mitochondrial function, Ca2+ handling, and antioxidant defenses during aging (Mattson et al., 2004). The decline in mitochondrial activity (Cai and Tammineni, 2017) and antioxidant defense mechanisms result in oxidation of proteins, lipids and DNA (Muller et al., 2018; Tonnies and Trushina, 2017), activation of microglia and the release of nitric oxide and pro-inflammatory cytokines (Bickford et al., 2017). In order to develop new strategies for preventing age-related decline in memory it is essential to understand the mechanisms underlying it at the cellular level in relevant brain areas.
Episodic and spatial memory decline in aging and are controlled by the hippocampus, perirhinal, frontal and parietal cortices and the connections between them. Ladostigil, a drug with antioxidant and anti-inflammatory activity, was shown to prevent the loss of episodic and spatial memory in aging rats. To better understand the molecular effects of aging and ladostigil on these brain regions we characterized the changes in gene expression using RNA-sequencing technology in rats aged 6 and 22 months. We found that the changes induced by aging and chronic ladostigil treatment were brain region specific. In the hippocampus, frontal and perirhinal cortex, ladostigil decreased the overexpression of genes regulating calcium homeostasis, ion channels and those adversely affecting synaptic function. In the parietal cortex, ladostigil increased the expression of several genes that provide neurotrophic support, while reducing that of pro-apoptotic genes and those encoding pro-inflammatory cytokines and their receptors. Ladostigil also decreased the expression of axonal growth inhibitors and those impairing mitochondrial function. Together, these actions could explain the protection by ladostigil against age-related memory decline.
Regulation of microglia by glutamate and its signal pathway in neurodegenerative diseases
2020, Drug Discovery Today
Microglia are an essential component of the central nervous system (CNS) and are involved in the primary response to microorganisms, neuroinflammation, homeostasis, and tissue regeneration, as well as contributing to the pathogenesis of neurodegenerative diseases. Research has shown that microglial diversity, multifunctionality, and their relationship with glutamate are crucial to determining their roles in these diseases. In this review, we focus on recent progress in determining microglial characteristics and the role of glutamate and its receptors in microglia regulation, which could be a novel therapeutic strategy for neurodegenerative diseases.
(-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer's disease challenged mice
2019, Neurobiology of Disease
Citation Excerpt :
In the light of the many drugs that demonstrate activity in a rodent model of TBI but then fail to show efficacy in humans, we additionally evaluated the ability of Phen to mitigate mTBI-induced changes in aged AD Tg mice. We hypothesized that these mice possess a particularly adverse brain microenvironment that may have more parallels to elderly humans (Bickford et al., 2017; von Bernhardi et al., 2015; d'Avila et al., 2018), and that TBI-induced changes would prove more of a challenge to mitigate (Becker and Greig, 2019). Although not a focus of the present study and not directly compared, aged AD Tg sham mice appeared to have a heightened level of neuroinflammation in contrast to that evident in younger WT mice in relation to IBA1-IR and colocalization with TNF-α.
Mild traumatic brain injury (mTBI) is a risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). TBI-derived neuropathologies are promoted by inflammatory processes: chronic microgliosis and release of pro-inflammatory cytokines that further promote neuronal dysfunction and loss. Herein, we evaluated the effect on pre-programmed cell death/neuroinflammation/synaptic integrity and function of (-)-Phenserine tartrate (Phen), an agent originally developed for AD. This was studied at two clinically translatable doses (2.5 and 5.0 mg/kg, BID), in a weight drop (concussive) mTBI model in wild type (WT) and AD APP/PSEN1 transgenic mice. Phen mitigated mTBI-induced cognitive impairment, assessed by Novel Object Recognition and Y-maze behavioral paradigms, in WT mice. Phen fully abated mTBI-induced neurodegeneration, evaluated by counting Fluoro-Jade C-positive (FJC+) cells, in hippocampus and cortex of WT mice. In APP/PSEN1 mice, degenerating cell counts were consistently greater across all experimental groups vs. WT mice. mTBI elevated FJC+ cell counts vs. the APP/PSEN1 control (sham) group, and Phen similarly mitigated this. Anti-inflammatory effects on microglial activation (IBA1-immunoreactivity (IR)) and the pro-inflammatory cytokine TNF-α were evaluated. mTBI increased IBA1-IR and TNF-α/IBA1 colocalization vs. sham, both in WT and APP/PSEN1 mice. Phen decreased IBA1-IR throughout hippocampi and cortices of WT mice, and in cortices of AD mice. Phen, likewise, reduced levels of IBA1/TNF-α-IR colocalization volume across all areas in WT animals, with a similar trend in APP/PSEN1 mice. Actions on astrocyte activation by mTBI were followed by evaluating GFAP, and were similarly mitigated by Phen. Synaptic density was evaluated by quantifying PSD-95+ dendritic spines and Synaptophysin (Syn)-IR. Both were significantly reduced in mTBI vs. sham in both WT and APP/PSEN1 mice. Phen fully reversed the PSD-95+ spine loss in WT and Syn-IR decrease in both WT and APP/PSEN1 mice. To associate immunohistochemical changes in synaptic markers with function, hippocampal long term potentiation (LTP) was induced in WT mice. LTP was impaired by mTBI, and this impairment was mitigated by Phen. In synopsis, clinically translatable doses of Phen ameliorated mTBI-mediated pre-programmed cell death/neuroinflammation/synaptic dysfunction in WT mice, consistent with fully mitigating mTBI-induced cognitive impairments. Phen additionally demonstrated positive actions in the more pathologic brain microenvironment of AD mice, further supporting consideration of its repurposing as a treatment for mTBI.

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Published by Elsevier Inc.

ReviewAging leads to altered microglial function that reduces brain resiliency increasing vulnerability to neurodegenerative diseases

Highlights

Abstract

Section snippets

Microglial changes with age

Impact of inflammation on neural plasticity

Approaches to modulating the systemic milieu and local inflammatory cell influences on the stem cell niche

Polyphenol rich diets effects on the system milieu with age

Polyphenol rich diets reduce microglial pro-inflammatory activation, increase neurogenesis, and improve learning in aged rats

Acknowledgements

Brain Behav. Immun.

Brain Res.

Lancet Neurol.

Neurobiol. Aging

J. Am. Med. Dir. Assoc.

Curr. Biol.

Neuropharmacology

Neurobiol. Aging

Exp. Neurol.

NT-020, a natural therapeutic approach to optimize spatial memory performance and increase neural progenitor cell proliferation and decrease inflammation in the aged rat

Rejuvenation Res.

Prevalence of Parkinsonian signs and associated mortality in a community population of older people

N. Engl. J. Med.

Polyphenols: multipotent therapeutic agents in neurodegenerative diseases

Oxidative Med. Cell. Longev.

Nutraceuticals synergistically promote proliferation of human stem cells

Stem Cells Dev.

Nutraceutical intervention reverses the negative effects of blood from aged rats on stem cells

Age (Dordr.)

SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1beta

J. Neurosci.

Rejuvenation of aged progenitor cells by exposure to a young systemic environment

Nature

IL-4 signaling drives a unique arginase +/IL-1beta + microglia phenotype and recruits macrophages to the inflammatory CNS: consequences of age-related deficits in IL-4Ralpha after traumatic spinal cord injury

J. Neurosci.

NT-020 treatment reduces inflammation and augments Nrf-2 and Wnt signaling in aged rats

J. Neuroinflammation

Diets enriched in foods with high antioxidant activity reverse age-induced decreases in cerebellar beta-adrenergic function and increases in proinflammatory cytokines

J. Neurosci.

Improvement of memory for context by inhibition of caspase-1 in aged rats

Eur. J. Neurosci.

Review
Aging leads to altered microglial function that reduces brain resiliency increasing vulnerability to neurodegenerative diseases