Every person with Down syndrome (DS) has the characteristic features of Alzheimer's disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people ...with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome-mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population.
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•Exosome technology can detect AD biomarkers decades prior to the onset of symptoms.•Exosome signaling and release are affected by both oxidative homeostasis and inflammation.•Exosomes may deliver therapies targeting oxidative stress, inflammation, and brain pathology.
Inflammation can be resolved by pro‐homeostatic lipids called specialized pro‐resolving mediators (SPMs) upon activation of their receptors. Dysfunctional inflammatory resolution is now considered as ...a driver of chronic neuroinflammation and Alzheimer's disease (AD) pathogenesis. We have previously shown that SPM levels were reduced and also that SPM‐binding receptors were increased in patients with AD compared to age‐matched controls. Individuals with Down syndrome (DS) exhibit accelerated acquisition of AD neuropathology, dementia, and neuroinflammation at an earlier age than the general population. Beneficial effects of inducing resolution in DS have not been investigated previously. The effects of the SPM resolvin E1 (RvE1) in a DS mouse model (Ts65Dn) were investigated with regard to inflammation, neurodegeneration, and memory deficits. A moderate dose of RvE1 for 4 weeks in middle‐aged Ts65Dn mice elicited a significant reduction in memory loss, along with reduced levels of serum pro‐inflammatory cytokines, and reduced microglial activation in the hippocampus of Ts65Dn mice but had no effects in age‐matched normosomic mice. There were no observable adverse side effects in Ts65Dn or in normosomic mice. These findings suggest that SPMs may represent a novel drug target for individuals with DS and others at risk of developing AD.
A specialized pro‐resolving mediator (SPM) contributed to the resolution of inflammation in the brain of an animal model for Down syndrome.
SPM activation of resolution prevented age‐related memory loss observed in Ts65Dn mice.
In order for Alzheimer's disease (AD) to manifest, cells must communicate "pathogenic material" such as proteins, signaling molecules, or genetic material to ensue disease propagation. Small ...extracellular vesicles are produced via the endocytic pathways and released by nearly all cell types, including neurons. Due to their intrinsic interrelationship with endocytic processes and autophagy, there has been increased interest in studying the role of these neuronally-derived extracellular vesicles (NDEVs) in the propagation of AD. Pathologic cargo associated with AD have been found in a number of studies, and NDEVs have been shown to induce pathogenesis in vivo and in vitro. Exogenous NDEVs are also shown to reduce plaque burden in AD models. Thus, the NDEV has the potential to become a useful biomarker, a pathologic potentiator, and a therapeutic opportunity. While the field of NDEV research in AD is still in its infancy, we review the current literature supporting these three claims.
Abstract Introduction Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology and dementia early in life. Blood biomarkers of AD neuropathology would be valuable, as ...non-AD intellectual disabilities of DS and AD dementia overlap clinically. We hypothesized that elevations of amyloid-β (Aβ) peptides and phosphorylated-tau in neuronal exosomes may document preclinical AD. Methods AD neuropathogenic proteins Aβ1–42 , P-T181-tau, and P-S396-tau were quantified by enzyme-linked immunosorbent assays in extracts of neuronal exosomes purified from blood of individuals with DS and age-matched controls. Results Neuronal exosome levels of Aβ1–42 , P-T181-tau, and P-S396-tau were significantly elevated in individuals with DS compared with age-matched controls at all ages beginning in childhood. No significant gender differences were observed. Discussion These early increases in Aβ1–42 , P-T181-tau, and P-S396-tau in individuals with DS may provide a basis for early intervention as targeted treatments become available.
Brain pericytes regulate cerebral blood flow, maintain the integrity of the blood-brain barrier (BBB), and facilitate the removal of amyloid β (Aβ), which is critical to healthy brain activity. ...Pericyte loss has been observed in brains from patients with Alzheimer's disease (AD) and animal models. Our previous data demonstrated that friend leukemia virus integration 1 (Fli-1), an erythroblast transformation-specific (ETS) transcription factor, governs pericyte viability in murine sepsis; however, the role of Fli-1 and its impact on pericyte loss in AD remain unknown. Here, we demonstrated that Fli-1 expression was up-regulated in postmortem brains from a cohort of human AD donors and in 5xFAD mice, which corresponded with a decreased pericyte number, elevated inflammatory mediators, and increased Aβ accumulation compared with cognitively normal individuals and wild-type (WT) mice. Antisense oligonucleotide Fli-1 Gapmer administered via intrahippocampal injection decelerated pericyte loss, decreased inflammatory response, ameliorated cognitive deficits, improved BBB dysfunction, and reduced Aβ deposition in 5xFAD mice. Fli-1 Gapmer-mediated inhibition of Fli-1 protected against Aβ accumulation-induced human brain pericyte apoptosis in vitro. Overall, these studies indicate that Fli-1 contributes to pericyte loss, inflammatory response, Aβ deposition, vascular dysfunction, and cognitive decline, and suggest that inhibition of Fli-1 may represent novel therapeutic strategies for AD.
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Fli-1 expression was significantly up-regulated in postmortem brains from patients with AD and in 5xFAD mice. Antisense oligonucleotide Fli-1 Gapmer decelerated pericyte loss, suppressed inflammatory response, ameliorated cognitive deficits, improved BBB function, and reduced Aβ deposition in 5xFAD mice. Thus, inhibition of Fli-1 may represent a novel therapeutic strategy for AD.
: Individuals with Down syndrome (DS) exhibit an almost complete penetrance of Alzheimer's disease (AD) pathology but are underrepresented in clinical trials for AD. The Tau protein is associated ...with microtubule function in the neuron and is crucial for normal axonal transport. In several different neurodegenerative disorders, Tau misfolding leads to hyper-phosphorylation of Tau (p-Tau), which may seed pathology to bystander cells and spread. This review is focused on current findings regarding p-Tau and its potential to seed pathology as a "prion-like" spreader. It also considers the consequences of p-Tau pathology leading to AD, particularly in individuals with Down syndrome.
: Scopus (SC) and PubMed (PM) were searched in English using keywords "tau AND seeding AND brain AND down syndrome". A total of 558 SC or 529 PM potentially relevant articles were identified, of which only six SC or three PM articles mentioned Down syndrome. This review was built upon the literature and the recent findings of our group and others.
: Misfolded p-Tau isoforms are seeding competent and may be responsible for spreading AD pathology.
: This review demonstrates recent work focused on understanding the role of neurofibrillary tangles and monomeric/oligomeric Tau in the prion-like spreading of Tau pathology in the human brain.
The accumulation of amyloid beta (Aβ) plaques in the brain is a hallmark of Alzheimer’s disease (AD) pathology. Microglial activation-mediated neuroinflammation has been implicated in the ...pathogenesis of AD and the expression levels of interleukin-6 (IL-6) were increased in the brains of AD patients. However, the mechanisms by which IL-6 expression is regulated in human microglia are incompletely understood. Here, we show that Aβ
1-40
oligomers (Aβ
40
) dose-dependently stimulate IL-6 expression in HMC3 human microglial cells. Treatment with Aβ
40
promotes the transcription of IL-6 and tumor necrosis factor α (TNFα) mRNAs in both HMC3 and THP-1 cells. Mechanistic studies reveal that Aβ
40
-induced increase of IL-6 secretion is associated with the activation of p38 mitogen-activated protein kinase (p38 MAPK). Inhibition of p38 MAPK by BIRB 796 or SB202190 abrogates Aβ
40
-induced increase of IL-6 production. Through analyzing brain specimens, we found that the immunoreactivity for IL-6 and phosphorylated (the activated form) p38 MAPK was markedly higher in microglia of AD patients than in age-matched control subjects. Moreover, our studies identified the co-localization of IL-6 with phosphorylated p38 MAPK in microglia in the cortices of AD patients. Taken together, these results indicate that p38 MAPK is a major regulator of Aβ-induced IL-6 production in human microglia, which suggests that targeting p38 MAPK may represent a new approach to ameliorate Aβ accumulation-induced neuroinflammation in AD.
The pontine nucleus locus coeruleus (LC) is the primary source of noradrenergic (NE) projections to the brain and is important for working memory, attention, and cognitive flexibility. Individuals ...with Down syndrome (DS) develop Alzheimer's disease (AD) with high penetrance and often exhibit working memory deficits coupled with degeneration of LC-NE neurons early in the progression of AD pathology. Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools that allow targeted manipulation of discrete neuronal populations in the brain without the confounds of off-target effects. We utilized male Ts65Dn mice (a mouse model for DS), and male normosomic (NS) controls to examine the effects of inhibitory DREADDs delivered via an AAV vector under translational control of the synthetic PRSx8, dopamine β hydroxylase (DβH) promoter. This chemogenetic tool allowed LC inhibition upon administration of the inert DREADD ligand, clozapine-N-oxide (CNO). DREADD-mediated LC inhibition impaired performance in a novel object recognition task and reversal learning in a spatial task. DREADD-mediated LC inhibition gave rise to an elevation of α-adrenoreceptors both in NS and in Ts65Dn mice. Further, microglial markers showed that the inhibitory DREADD stimulation led to increased microglial activation in the hippocampus in Ts65Dn but not in NS mice. These findings strongly suggest that LC signaling is important for intact memory and learning in Ts65Dn mice and disruption of these neurons leads to increased inflammation and dysregulation of adrenergic receptors.
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•Loss of LC-NE activity may be an early event Alzheimer's disease (AD) especially for individuals with Down syndrome (DS).•Targeted designer receptors (DREADDs) allow specific and complete inhibition of DβH-expressing LC neurons.•LC signaling regulates microglial activation in a DS mouse model.•Ts65Dn mice exhibit alterations in adrenergic receptor staining before degeneration of LC neurons at 4 months of age.
Down syndrome (DS) is the most common non-lethal genetic condition that affects approximately 1 in 700 births in the United States of America. DS is characterized by complete or segmental chromosome ...21 trisomy, which leads to variable intellectual disabilities, progressive memory loss, and accelerated neurodegeneration with age. During the last three decades, people with DS have experienced a doubling of life expectancy due to progress in treatment of medical comorbidities, which has allowed this population to reach the age when they develop early onset Alzheimer's disease (AD). Individuals with DS develop cognitive and pathological hallmarks of AD in their fourth or fifth decade, and are currently lacking successful prevention or treatment options for dementia. The profound memory deficits associated with DS-related AD (DS-AD) have been associated with degeneration of several neuronal populations, but mechanisms of neurodegeneration are largely unexplored. The most successful animal model for DS is the Ts65Dn mouse, but several new models have also been developed. In the current review, we discuss recent findings and potential treatment options for the management of memory loss and AD neuropathology in DS mouse models. We also review agerelated neuropathology, and recent findings from neuroimaging studies. The validation of appropriate DS mouse models that mimic neurodegeneration and memory loss in humans with DS can be valuable in the study of novel preventative and treatment interventions, and may be helpful in pinpointing gene-gene interactions as well as specific gene segments involved in neurodegeneration.
Slowed information processing speed is a defining feature of cognitive aging. Nucleus locus coeruleus (LC) and medial prefrontal regions are targets for understanding slowed processing speed because ...these brain regions influence neural and behavioral response latencies through their roles in optimizing task performance. Although structural measures of medial prefrontal cortex have been consistently related to processing speed, it is unclear if 1) declines in LC structure underlie this association because of reciprocal connections between LC and medial prefrontal cortex, or 2) if LC declines provide a separate explanation for age-related changes in processing speed. LC and medial prefrontal structural measures were predicted to explain age-dependent individual differences in processing speed in a cross-sectional sample of 43 adults (19–79 years; 63% female). Higher turbo-spin echo LC contrast, based on a persistent homology measure, and greater dorsal cingulate cortical thickness were significantly and each uniquely related to faster processing speed. However, only dorsal cingulate cortical thickness appeared to statistically mediate age-related differences in processing speed. The results suggest that individual differences in cognitive processing speed can be attributed, in part, to structural variation in nucleus LC and medial prefrontal cortex, with the latter key to understanding why older adults exhibit slowed processing speed.
•Locus coeruleus (LC) contrast predicted processing speed.•Dorsal cingulate cortical thickness predicted processing speed.•LC and dorsal cingulate were related to age in this adult sample.•Dorsal cingulate mediated age-dependent differences in processing speed.
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