Microglia affect Alzheimer's disease (AD) pathogenesis in opposing manners, by protecting against amyloid accumulation in early phases of the disease and promoting neuropathology in advanced stages. ...Recent research has identified specific microglial interactions with amyloid plaques that exert important protective functions including attenuation of early pathology. It is unknown how these protective microglial interactions with plaques are affected by apolipoprotein E (APOE) genotype and sex, two well-established AD risk factors that modulate microglial function. We investigated this question using quantitative confocal microscopy to compare microglial interactions with amyloid plaques in male and female EFAD mice across APOE3 and APOE4 genotypes at 6 months of age. We observed that microglial coverage of plaques is highest in male APOE3 mice with significant reductions in coverage observed with both APOE4 genotype and female sex. Plaque compaction, a beneficial consequence of microglial interactions with plaques, showed a similar pattern in which APOE4 genotype and female sex were associated with significantly lower values. Within the plaque environment, microglial expression of triggering receptor expressed on myeloid cells 2 (TREM2), a known regulator of microglial plaque coverage, was highest in male APOE3 mice and reduced by APOE4 genotype and female sex. These differences in plaque interactions were unrelated to the number of microglial processes in the plaque environment across groups. Interestingly, the pattern of amyloid burden across groups was opposite to that of microglial plaque coverage, with APOE4 genotype and female sex showing the highest amyloid levels. These findings suggest a possible mechanism by which microglia may contribute to the increased AD risk associated with APOE4 genotype and female sex.
Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer's disease (AD). ...Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women's Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice (5xFAD
/human APOE ɛ3 or ɛ4
) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral β-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aβ deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aβ oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aβ production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.
Neuronal plasticity is regulated by the ovarian steroids estradiol (E2) and progesterone (P4) in many normal brain functions, as well as in acute response to injury and chronic neurodegenerative ...disease. In a female rat model of axotomy, the E2-dependent compensatory neuronal sprouting is antagonized by P4. To resolve complex glial-neuronal cell interactions, we used the “wounding-in-a-dish” model of neurons cocultured with astrocytes or mixed glia (microglia to astrocytes, 1:3). Although both astrocytes and mixed glia supported E2-enhanced neurite outgrowth, P4 antagonized E2-induced neurite outgrowth only with mixed glia, but not astrocytes alone. We now show that P4-E2 antagonism of neurite outgrowth is mediated by microglial expression of progesterone receptor (Pgr) membrane component 1 (Pgrmc1)/S2R, a putative nonclassical Pgr mediator with multiple functions. The P4-E2 antagonism of neurite outgrowth was restored by add-back of microglia to astrocyte-neuron cocultures. Because microglia do not express the classical Pgr, we examined the role of Pgrmc1, which is expressed in microglia in vitro and in vivo. Knockdown by siRNA-Pgrmc1 in microglia before add-back to astrocyte-neuron cocultures suppressed the P4-E2 antagonism of neurite outgrowth. Conditioned media from microglia restored the P4-E2 activity, but only if microglia were activated by lipopolysaccharide or by wounding. Moreover, the microglial activation was blocked by Pgmrc1-siRNA knockdown. These findings explain why nonwounded cultures without microglial activation lack P4 antagonism of E2-induced neurite outgrowth. We suggest that microglial activation may influence brain responses to exogenous P4, which is a prospective therapy in traumatic brain injury.
Exposure to traffic-related air pollution (TRAP) is associated with a range of neurodevelopmental disorders in human populations. In rodent models, prenatal TRAP exposure increased depressive ...behaviors and increased brain microglial activity. To identify cellular mechanisms, we examined adult neurogenesis and the blood-brain barrier (BBB) in relation to cognition and motivated behaviors in rats that were exposed to a nano-sized TRAP subfraction from gestation into adulthood. At age 5 months, exposed male rats had 70% fewer newly generated neurons in the dentate gyrus (DG) of the hippocampus. Microglia were activated in DG and CA1 subfields (35% more Iba1). The BBB was altered, with a 75% decrease of the tight junction protein ZO-1 in the CA1 layer, and twofold more iron deposits, a marker of microhemorrhages. The exposed rats had impaired contextual memory (novel object in context), reduced food-seeking behavior, and increased depressive behaviors (forced swim). Deficits of de novo neurogenesis were inversely correlated with depressive behavior, whereas increased microbleeds were inversely correlated with deficits in contextual memory. These findings give the first evidence that prenatal and early life exposure to TRAP impairs adult hippocampal neurogenesis and increases microbleeds in association with behavioral deficits.
Seed functional traits of native Helianthus species contribute towards ecosystem services but limitations to their use in managed programmes exist. Many perennial Helianthus possess seed dormancy. ...The ability for germination to occur under different temperature and drought conditions, as well as the capacity of germinated seeds to convert into normal seedlings is rarely considered. Our aim was to identify and quantify these constraints through functional trait analyses. In five seed lots of native Helianthus (four perennial and one annual) and five genotypes of sunflower (H. annuus) for comparison, dormancy, thermal and hydro thresholds and times, morphology, mass, oil content and conversion into normal seedlings were quantified. The influence of the seed collection site environment on these traits was also explored. Seed dormancy of the perennial species was overcome by scarification followed by germination in 5 mm GA
. Thermal and hydro-time analyses revealed slower germination for the native seed lots (>1350 °Ch) in comparison to the sunflower genotypes (<829.9 °Ch). However, native seed lots had a higher capacity to convert into normal seedlings at high temperatures and low water potentials than sunflower genotypes. For the native seed lots, the average monthly temperature of the collection site was negatively correlated with thermal time. Variability in seed functional traits of native Helianthus and greater capacity for germinated seeds to convert into normal seedlings suggests they are better equipped to cope with high temperature and drought scenarios than sunflower. Effective dormancy alleviation is required to facilitate the use of native Helianthus species.
Genetics of Aging Finch, Caleb E.; Tanzi, Rudolph E.
Science (American Association for the Advancement of Science),
10/1997, Letnik:
278, Številka:
5337
Journal Article
Recenzirano
The role of genetics in determining life-span is complex and paradoxical. Although the heritability of life-span is relatively minor, some genetic variants significantly modify senescence of mammals ...and invertebrates, with both positive and negative impacts on age-related disorders and life-spans. In certain examples, the gene variants alter metabolic pathways, which could thereby mediate interactions with nutritional and other environmental factors that influence life-span. Given the relatively minor effect and variable penetrance of genetic risk factors that appear to affect survival and health at advanced ages, life-style and other environmental influences may profoundly modify outcomes of aging.
Barbi
(Reports, 29 June 2018, p. 1459) reported that human mortality rate reached a "plateau" after the age of 105, suggesting there may be no limit to human longevity. We show, using their data, ...that potential lifespans cannot increase much beyond the current 122 years unless future biomedical advances alter the intrinsic rate of human aging.
Pgrmc1 (progesterone receptor membrane component 1) is a multifunctional 22 kDa protein with heme-binding and P450-activating capacity which was recognized under different names for roles in cell ...motility during neural development and in cancer, and apoptosis. Pgrmc1 expression in microglia was recently shown by the present authors to mediate estrogen-progesterone interactions during axonal sprouting and to mediate microglial activation itself. We also discuss other functions of Pgramc1 in the nervous system and its possible relationship to the 18 kDa sigma-2 receptor (S2R).
Abstract Traffic-related air pollution (TRAP) is associated with lower cognition and reduced white matter volume in older adults, specifically for particulate matter <2.5-μm diameter (PM2.5 ). ...Rodents exposed to TRAP have shown microglial activation and neuronal atrophy. We further investigated age differences of TRAP exposure, with focus on hippocampus for neuritic atrophy, white matter degeneration, and microglial activation. Young- and middle-aged mice (3 and 18 months female C57BL/6J) were exposed to nanoscale-PM (nPM, <0.2 μm diameter). Young mice showed selective changes in the hippocampal CA1 region, with neurite atrophy (−25%), decreased MBP (−50%), and increased Iba1 (+50%), with dentate gyrus relatively unaffected. Exposure to nPM of young mice decreased GluA1 protein (−40%) and increased TNFa mRNA (10×). Older controls had age changes approximating nPM effects on young, with no response to nPM, suggesting an age-ceiling effect. The CA1 selective vulnerability in young mice parallels CA1 vulnerability in Alzheimer's disease. We propose that TRAP-associated human cognitive and white matter changes involve hippocampal responses to nPM that begin at younger ages.
THE GENETICS OF AGING Finch, Caleb E; Ruvkun, Gary
Annual review of genomics and human genetics,
01/2001, Letnik:
2, Številka:
1
Journal Article
Recenzirano
The genetic analysis of life span has only begun in mammals, invertebrates,
such as
Caenorhabditis elegans
and
Drosophila
, and yeast. Even at
this primitive stage of the genetic analysis of aging, ...the physiological
observations that rate of metabolism is intimately tied to life span is
supported. In many examples from mice to worms to flies to yeast, genetic
variants that affect life span also modify metabolism. Insulin signaling
regulates life span coordinately with reproduction, metabolism, and free
radical protective gene regulation in
C. elegans
. This may be related to
the findings that caloric restriction also regulates mammalian aging, perhaps
via the modulation of insulin-like signaling pathways. The nervous system has
been implicated as a key tissue where insulin-like signaling and free radical
protective pathways regulate life span in
C. elegans
and
Drosophila
. Genes that determine the life span could act in
neuroendocrine cells in diverse animals. The involvement of insulin-like
hormones suggests that the plasticity in life spans evident in animal phylogeny
may be due to variation in the timing of release of hormones that control
vitality and mortality as well as variation in the response to those hormones.
Pedigree analysis of human aging may reveal variations in the orthologs of the
insulin pathway genes and coupled pathways that regulate invertebrate aging.
Thus, genetic approaches may identify a set of circuits that was established in
ancestral metazoans to regulate their longevity.
PDF
