To determine the stability of beta-amyloid peptide (Abeta) and the glial and neuronal changes induced by Abeta in the CNS in vivo, we made single injections of fibrillar Abeta (fAbeta), soluble Abeta (sAbeta), or vehicle into the rat striatum. Injected fAbeta is stable in vivo for at least 30 d after injection, whereas sAbeta is primarily cleared within 1 d. After injection of fAbeta, microglia phagocytize fAbeta aggregates, whereas nearby astrocytes form a virtual wall between fAbeta-containing microglia and the surrounding neuropil. Similar glial changes are not observed after sAbeta injection. Microglia and astrocytes near the injected fAbeta show a significant increase in inducible nitric oxide synthase (iNOS) expression compared with that seen with sAbeta or vehicle injection. Injection of fAbeta but not sAbeta or vehicle induces a significant loss of parvalbumin- and neuronal nitric oxide synthase-immunoreactive neurons, whereas the number of calbindin-immunoreactive neurons remains unchanged. These data demonstrate that fAbeta is remarkably stable in the CNS in vivo and suggest that fAbeta neurotoxicity is mediated in large part by factors released from activated microglia and astrocytes, as opposed to direct interaction between Abeta fibrils and neurons.
A small, orally available natural product penetrates into the brain in vivo to rescue the memory impairment produced by soluble Abeta oligomers through a mechanism that restores hippocampal synaptic plasticity.
Quantification of nanoparticles in biological systems (i.e., cells, tissues and organs) is becoming a vital part of nanotoxicological and nanomedical fields. Dose is a key parameter when assessing behavior and any potential risk of nanomaterials. Various techniques for nanoparticle quantification in cells and tissues already exist but will need further development in order to make measurements reliable, reproducible and intercomparable between different techniques. Microscopy allows detection and location of nanoparticles in cells and has been used extensively in recent years to characterize nanoparticles and their pathways in living systems. Besides microscopical techniques (light microscopy and electron microscopy mainly), analytical techniques such as mass spectrometry, an established technique in trace element analysis, have been used in nanoparticle research. Other techniques require 'labeled' particles, fluorescently, radioactively or magnetically. However, these techniques lack spatial resolution and subcellular localization is not possible. To date, only electron microscopy offers the resolving power to determine accumulation of nanoparticles in cells due to its ability to image particles individually. So-called super-resolution light microscopy techniques are emerging to provide sufficient resolution on the light microscopy level to image or 'see' particles as individual particles. Nevertheless, all microscopy techniques require statistically sound sampling strategies in order to provide quantitative results. Stereology is a well-known sampling technique in various areas and, in combination with electron microscopy, proves highly successful with regard to quantification of nanoparticle uptake by cells.
Amyloid β‐peptides (Aβ) may alter the neuronal membrane lipid environment by changing fluidity and inducing free radical lipid peroxidation. The effects of Aβ1–40 and Aβ25–35 on the fluidity of lipids adjacent to proteins (annular fluidity), bulk lipid fluidity, and lipid peroxidation were determined in rat synaptic plasma membranes (SPM). A fluorescent method based on radiationless energy transfer from tryptophan of SPM proteins to pyrene and pyrene monomer‐eximer formation was used to determine SPM annular fluidity and bulk fluidity, respectively. Lipid peroxidation was determined by the thiobarbituric acid assay. Annular fluidity and bulk fluidity of SPM were increased significantly (p≤ 0.02) by Aβ1–40. Similar effects on fluidity were observed for Aβ25–35 (p≤ 0.002). Increased fluidity was associated with lipid peroxidation. Both Aβ peptides significantly increased (p≤ 0.006) the amount of malondialdehyde in SPM. The addition of a water‐soluble analogue of vitamin E (Trolox) inhibited effects of Aβ on lipid peroxidation and fluidity in SPM. The fluidizing action of Aβ peptides on SPM may be due to the induction of lipid peroxidation by those peptides. Aβ‐induced changes in neuronal function, such as ion flux and enzyme activity, that have been reported previously may result from the combined effects of lipid peroxidation and increased membrane fluidity.
Converging lines of evidence suggest that oligomers of amyloid-β play a role in the cognitive impairment characteristic of Alzheimer's disease, but only three studies have provided experimental evidence of such impairment. To provide additional information about the effects of these oligomers on memory, the present study examined the memory of groups of rats exposed to ICV injections of the culture media (CM) of Chinese Hamster Ovary cells that were (7PA2) and were not (CHO-) transfected with a human mutation of amyloid precursor protein that appears to cause early-onset Alzheimer's disease. The 7PA2 CM, which contained concentrations of soluble amyloid-β oligomers physiologically relevant to those found in human brain, significantly disrupted working memory in rats tested in a radial-arm maze. In contrast, CHO-CM, which did not contain such oligomers, had no effect on memory. The disruptive effects of 7PA2-derived amyloid-β oligomers, evident two hours after exposure, disappeared within a day. These findings are compared to results from 7PA2 CM tested under a complex procedure thought to measure aspects of executive function. The results confirm the disruptive effects of low-n amyloid-β oligomers and extend them to a well established rat model of memory.
The opioid system plays an important role in feeding. In general, opioid agonists typically increase feeding and opioid antagonists decrease feeding in non-food restricted animals. In food restricted animals the effects of these drugs are substantially reduced. Opioid antagonists have shown a marked effectiveness at reducing consumption of sweet foods. Explanations for this robust effect have typically focused on drug induced changes in taste, taste perception, or palatability. The current study relates the effects of the opioid antagonist naloxone on motivation to obtain different sucrose concentrations to the drug's effects on unrestricted sucrose solution consumption. Changes in motivation to respond were assessed under a progressive ratio reinforcement schedule (PR) which required increased response cost for each successive unit of sucrose solution. Motivation, as measured by the PR, increased as sucrose concentration increased and naloxone produced a dose-dependent decrease in motivation to respond for a given sucrose concentration. Thus, the effectiveness of naloxone was indirectly related to strength of the sucrose concentration. Under unrestricted access to sucrose solutions, naloxone reduced consumption greatest under the higher concentrations. The data suggest at least part of naloxone's effects on sweet tasting food may be mediated through endogenous opioid reward systems that are reflected in measures of motivation.
We studied the effect of the opioid receptor antagonist naloxone on intake of three isocaloric diets containing cornstarch, sucrose, or Polycose as the predominant carbohydrate in ad libitum-fed and food-restricted rats. A large body of evidence suggests that opioids affect palatability (reward)-rater than hunger (energy deficit)-driven food intake. We expected food intake to be driven by both energy needs and palatability in ad libitum-fed rats, whereas in food-restricted rats we expected intake to be driven by energy needs with a relatively small palatability component in the preferred sucrose and Polycose diet groups. In the ad libitum-fed rats, naloxone significantly reduced nocturnal intake of all three diets at doses of 0.3, 1.0, and 3.0 mg/kg. In contrast, naloxone failed to alter intake of the cornstarch diet in chronically food-restricted rats. However, naloxone decreased intake of the sucrose diet in food-restricted rats at doses of 0.3, 1.0, and 3.0 mg/kg and decreased intake of the Polycose diet at the 3 mg/kg dose. These data lend further support to the notion that opioids are involved in some other component of feeding than that induced by energy needs.
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