Changes in insulin and insulin signaling in Alzheimer\u27s disease: Cause or consequence?

Individuals with type 2 diabetes have an increased risk for developing Alzheimer’s disease (AD), although the causal relationship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils of amyloid-β (Aβ) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aβ levels and tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause or consequence of AD

Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-β accumulation and independently accelerates the development of tau abnormalities

Alzheimer\u27s disease (AD) is a neurodegenerative disorder characterized pathologically by progressive neuronal loss, extracellular plaques containing the amyloid-β (Aβ) peptides, and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Aβ is thought to act upstream of tau, affecting its phosphorylation and therefore aggregation state. One of the major risk factors for AD is traumatic brain injury (TBI). Acute intra-axonal Aβ and diffuse extracellular plaques occur in ∼30% of human subjects after severe TBI. Intra-axonal accumulations of tau but not tangle-like pathologies have also been found in these patients. Whether and how these acute accumulations contribute to subsequent AD development is not known, and the interaction between Aβ and tau in the setting of TBI has not been investigated. Here, we report that controlled cortical impact TBI in 3xTg-AD mice resulted in intra-axonal Aβ accumulations and increased phospho-tau immunoreactivity at 24 h and up to 7 d after TBI. Given these findings, we investigated the relationship between Aβ and tau pathologies after trauma in this model by systemic treatment of Compound E to inhibit γ-secretase activity, a proteolytic process required for Aβ production. Compound E treatment successfully blocked posttraumatic Aβ accumulation in these injured mice at both time points. However, tau pathology was not affected. Our data support a causal role for TBI in acceleration of AD-related pathologies and suggest that TBI may independently affect Aβ and tau abnormalities. Future studies will be required to assess the behavioral and long-term neurodegenerative consequences of these pathologies

Determining Ages of APOGEE Giants with Known Distances

We present a sample of local red giant stars observed using the New Mexico State University 1 m telescope with the APOGEE spectrograph, for which we estimate stellar ages and the age distribution from the high-resolution spectroscopic stellar parameters and accurate distance measurements from Hipparcos. The high-resolution (R ~ 23,000), near infrared (H-band, 1.5-1.7 micron) APOGEE spectra provide measurements of the stellar atmospheric parameters (temperature, surface gravity, [M/H], and [alpha/M]). Due to the smaller uncertainties in surface gravity possible with high-resolution spectra and accurate Hipparcos distance measurements, we are able to calculate the stellar masses to within 40%. For red giants, the relatively rapid evolution of stars up the red giant branch allows the age to be constrained based on the mass. We examine methods of estimating age using both the mass-age relation directly and a Bayesian isochrone matching of measured parameters, assuming a constant star formation history (SFH). To improve the prior on the SFH, we use a hierarchical modeling approach to constrain the parameters of a model SFH from the age probability distribution functions of the data. The results of an alpha dependent Gaussian SFH model shows a clear relation between age and [alpha/M] at all ages. Using this SFH model as the prior for an empirical Bayesian analysis, we construct a full age probability distribution function and determine ages for individual stars. The age-metallicity relation is flat, with a slight decrease in [M/H] at the oldest ages and a ~ 0.5 dex spread in metallicity. For stars with ages < 1 Gyr we find a smaller spread, consistent with radial migration having a smaller effect on these young stars than on the older stars.Comment: 14 page, 18 figures, accepted to ApJ with minor revisions, full electronic table of data available upon publicatio

The stellar population structure of the Galactic disk

The spatial structure of stellar populations with different chemical abundances in the Milky Way contains a wealth of information on Galactic evolution over cosmic time. We use data on 14,699 red-clump stars from the APOGEE survey, covering 4 kpc <~ R <~ 15 kpc, to determine the structure of mono-abundance populations (MAPs)---stars in narrow bins in [a/Fe] and [Fe/H]---accounting for the complex effects of the APOGEE selection function and the spatially-variable dust obscuration. We determine that all MAPs with enhanced [a/Fe] are centrally concentrated and are well-described as exponentials with a scale length of 2.2+/-0.2 kpc over the whole radial range of the disk. We discover that the surface-density profiles of low-[a/Fe] MAPs are complex: they do not monotonically decrease outwards, but rather display a peak radius ranging from ~5 kpc to ~13 kpc at low [Fe/H]. The extensive radial coverage of the data allows us to measure radial trends in the thickness of each MAP. While high-[a/Fe] MAPs have constant scale heights, low-[a/Fe] MAPs flare. We confirm, now with high-precision abundances, previous results that each MAP contains only a single vertical scale height and that low-[Fe/H], low-[a/Fe] and high-[Fe/H], high-[a/Fe] MAPs have intermediate (h_Z~300 to 600 pc) scale heights that smoothly bridge the traditional thin- and thick-disk divide. That the high-[a/Fe], thick disk components do not flare is strong evidence against their thickness being caused by radial migration. The correspondence between the radial structure and chemical-enrichment age of stellar populations is clear confirmation of the inside-out growth of galactic disks. The details of these relations will constrain the variety of physical conditions under which stars form throughout the MW disk.Comment: Code available at https://github.com/jobovy/apogee-map

Imprints of radial migration on the Milky Way’s metallicity distribution functions

Recent analysis of the SDSS-III/Apache Point Observatory Galactic Evolution Experiment (APOGEE) Data Release 12 stellar catalog has revealed that the Milky Way’s (MW) metallicity distribution function (MDF) changes shape as a function of radius, transitioning from being negatively skewed at small Galactocentric radii to positively skewed at large Galactocentric radii. Using a high-resolution, N-body+SPH simulation, we show that the changing skewness arises from radial migration—metal-rich stars form in the inner disk and subsequently migrate to the metal-poorer outer disk. These migrated stars represent a large fraction (>50%) of the stars in the outer disk; they populate the high-metallicity tail of the MDFs and are, in general, more metal-rich than the surrounding outer disk gas. The simulation also reproduces another surprising APOGEE result: the spatially invariant high-[α/Fe] MDFs. This arises in the simulation from the migration of a population formed within a narrow range of radii (3.2 ±1.2 kpc) and time (8.8 ± 0.6 Gyr ago), rather than from spatially extended star formation in a homogeneous medium at early times. These results point toward the crucial role radial migration has played in shaping our MW

Translocator protein in late stage Alzheimer\u27s disease and Dementia with Lewy bodies brains

OBJECTIVE: Increased translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), in glial cells of the brain has been used as a neuroinflammation marker in the early and middle stages of neurodegenerative diseases, such as Alzheimer\u27s disease (AD) and Dementia with Lewy Bodies (DLB). In this study, we investigated the changes in TSPO density with respect to late stage AD and DLB. METHODS: TSPO density was measured in multiple regions of postmortem human brains in 20 different cases: seven late stage AD cases (Braak amyloid average: C; Braak tangle average: VI; Aged 74-88, mean: 83 ± 5 years), five DLB cases (Braak amyloid average: C; Braak tangle average: V; Aged 79-91, mean: 84 ± 4 years), and eight age-matched normal control cases (3 males, 5 females: aged 77-92 years; mean: 87 ± 6 years). Measurements were taken by quantitative autoradiography using [ RESULTS: No significant changes were found in TSPO density of the frontal cortex, striatum, thalamus, or red nucleus of the AD and DLB brains. A significant reduction in TSPO density was found in the substantia nigra (SN) of the AD and DLB brains compared to that of age-matched healthy controls. INTERPRETATION: This distinct pattern of TSPO density change in late stage AD and DLB cases may imply the occurrence of microglia dystrophy in late stage neurodegeneration. Furthermore, TSPO may not only be a microglia activation marker in early stage AD and DLB, but TSPO may also be used to monitor microglia dysfunction in the late stage of these diseases

The effects of peripheral and central high insulin on brain insulin signaling and amyloid-β in young and old APP/PS1 mice

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP(swe)/PS1(dE9) transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE STATEMENT The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections between high insulin and extracellular Aβ, but these mechanisms presume that peripheral high insulin elevates brain insulin significantly. We found that physiological hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an appreciable level yet modestly increases extracellular Aβ. We also found that the brain of aged APP/PS1 mice was not insulin resistant, contrary to the current state of the literature. These results further elucidate the relationship between insulin, the brain, and AD and its conflicting roles as both a risk factor and potential treatment

Loss of intranetwork and internetwork resting state functional connections with Alzheimer\u27s disease progression

Alzheimer\u27s disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD research has used resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n = 510) that ranged in AD severity from unaffected [clinical dementia rating (CDR) 0] to very mild (CDR 0.5) to mild (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intranetwork and internetwork correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brain\u27s functional organization

Chemical tagging can work: Identification of stellar phase-space structures purely by chemical-abundance similarity

Chemical tagging promises to use detailed abundance measurements to identify spatially separated stars that were in fact born together (in the same molecular cloud), long ago. This idea has not yielded much practical success, presumably because of the noise and incompleteness in chemical-abundance measurements. We have succeeded in substantially improving spectroscopic measurements with The Cannon, which has now delivered 15 individual abundances for ~100,000 stars observed as part of the APOGEE spectroscopic survey, with precisions around 0.04 dex. We test the chemical-tagging hypothesis by looking at clusters in abundance space and confirming that they are clustered in phase space. We identify (by the k-means algorithm) overdensities of stars in the 15-dimensional chemical-abundance space delivered by The Cannon, and plot the associated stars in phase space. We use only abundance-space information (no positional information) to identify stellar groups. We find that clusters in abundance space are indeed clusters in phase space. We recover some known phase-space clusters and find other interesting structures. This is the first-ever project to identify phase-space structures at survey-scale by blind search purely in abundance space; it verifies the precision of the abundance measurements delivered by The Cannon; the prospects for future data sets appear very good.Comment: accepted for publication in the Ap

Opposing synaptic regulation of amyloid-β metabolism by NMDA receptors in vivo

The concentration of amyloid-β (Aβ) within the brain extracellular space is one determinant of whether the peptide will aggregate into toxic species that are important in Alzheimer’s disease (AD) pathogenesis. Some types of synaptic activity can regulate Aβ levels. Here we demonstrate two distinct mechanisms that are simultaneously activated by NMDA receptors and regulate brain interstitial fluid (ISF) Aβ levels in opposite directions in the living mouse. Depending on the dose of NMDA administered locally to the brain, ISF Aβ levels either increase or decrease. Low doses of NMDA increase action potentials and synaptic transmission which leads to an elevation in synaptic Aβ generation. In contrast, high doses of NMDA activate signaling pathways that lead to ERK (extracellular-regulated kinase) activation, which reduces processing of APP into Aβ. This depression in Aβ via APP processing occurs despite dramatically elevated synaptic activity. Both of these synaptic mechanisms are simultaneously active, with the balance between them determining whether ISF Aβ levels will increase or decrease. NMDA receptor antagonists increase ISF Aβ levels, suggesting that basal activity at these receptors normally suppresses Aβ levels in vivo. This has implications for understanding normal Aβ metabolism as well as AD pathogenesis