Summary Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of β-amyloid (Aβ) peptide, ultimately leading to formation of Aβ plaques in the brain. This process occurs while individuals are still cognitively normal. Biomarkers of brain β-amyloidosis are reductions in CSF Aβ 42 and increased amyloid PET tracer retention. After a lag period, which varies from patient to patient, neuronal dysfunction and neurodegeneration become the dominant pathological processes. Biomarkers of neuronal injury and neurodegeneration are increased CSF tau and structural MRI measures of cerebral atrophy. Neurodegeneration is accompanied by synaptic dysfunction, which is indicated by decreased fluorodeoxyglucose uptake on PET. We propose a model that relates disease stage to AD biomarkers in which Aβ biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.

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Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade

Functional brain imaging in humans has revealed task-specific increases in brain activity that are associated with various mental activities. In the same studies, mysterious, task-independent decreases have also frequently been encountered, especially when the tasks of interest have been compared with a passive state, such as simple fixation or eyes closed. These decreases have raised the possibility that there might be a baseline or resting state of brain function involving a specific set of mental operations. We explore this possibility, including the manner in which we might define a baseline and the implications of such a baseline for our understanding of brain function.

https://www.biac.duke.edu/education/courses/fall04/fmri/readings/week10/2001_NatRevNeuro_Gusnard.pdf

Searching for a baseline: Functional imaging and the resting human brain

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via Gq proteins to phospholipase C-β. The high-affinity receptor state requires both Mg2+ and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has bee...

The Oxytocin Receptor System: Structure, Function, and Regulation

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

https://www.cell.com/cell/pdf/S0092-8674(02)00722-5.pdf

Coordinated transcription of key pathways in the mouse by the circadian clock.

Studies on bursting pacemaker potential activity in molluscan neurons. III. Effects of hormones.

[35S]Cysteine injected adjacent to the supraoptic nucleus of the rat is rapidly incorporated into a 20,000-dalton protein that, in time, is converted to a 12,000-dalton labeled protein, neurophysin. This putative precursor of neurophysin appears to be synthesized in the supraoptic nucleus and transformed to neurophysin and related peptides during axonal transport to the neurohypophysis.

https://science.sciencemag.org/content/sci/195/4284/1354.full.pdf

Neurophysin Biosynthesis: Conversion of a Putative Precursor During Axonal Transport

[35S]Cysteine-labeled putative precursors for vasopressin-associated neurophysin (NP-VP) and oxytocin-associated neurophysin (NP-OT) were isolated from the supraoptic nuclei (SONs) of normal rats. Homozygous Brattleboro rats were deficient in one of these precursors, the NP-VP precursor. Direct support for the hypothesis that OT and its NP- and VP and its NP are synthesized from two separate macromolecular common precursors was obtained by limited proteolysis of the precursors with trypsin and identification of the fragments as NPs, VP, or OT by a number of criteria (14). In this paper, these common precursors designated propressophysin (precursor for NP-VP and arginine VP) and prooxyphysin (precursor for NP-OT and OT) were further characterized. Propressophysin was specifically bound by Concanavalin-A-Sepharose and was eluted by 0.2 M alpha-methyl mannoside, showing that it is glycosylated. In contrast, prooxyphysin does not appear to be glycosylated. Using [3H]fucose as label injected near the SONs, two proteins (mol wt, approximately 10,000) were identified, which appear to be derived from propressophysin, that are rapidly transported to the posterior pituitary of normal rats. These two proteins were absent in homozygous Brattleboro animals. Both propressophysin and prooxyphysin were bound by a NP-Sepharose affinity support. The binding was different from that of arginine VP or OT to NP, since it was independent of pH and was hydrophobic in nature. In addition to prooxyphysin, the SONs of homozygous Brattleboro rats also contained other [35S]cysteine-labeled protein (mol wt, 20,000) composed of a NP-like protein and NP-binding peptides. The tryptic peptides derived from these proteins were very different in their chromatographic (high performance liquid chromatography) properties than the tryptic peptides derived from propressophysin and prooxyphysin. This protein ('X') was not bound by a Concanavalin-A-Sepharose affinity column, although it had chromatographic properties similar to propressophysin on Sephadex G-75.

Biosynthesis of Vasopressin, Oxytocin, and Neurophysins: Isolation and Characterization of Two Common Precursors (Propressophysin and Prooxyphysin)

Incubation of intracellulary perfused squid giant axons in [3H]leucine demonstrated that newly synthesized proteins appeared in the perfusate after a 45-min lag period. The transfer of labeled proteins was shown to occur steadily over 8 h of incubation, in the presence of an intact axonal plasma membrane as evidenced by the ability of the perfused axon to conduct propagated action potentials over this time-period. Intracellularly perfused RNase did not affect this transfer, whereas extracellularly applied puromycin, which blocked de novo protein synthesis in the glial sheath, prevented the appearance of labeled proteins in the perfusate. The uptake of exogenous 14C-labeled bovine serum albumin (BSA) into the axon had entirely different kinetics than the endogenous glial labeled protein transfer process. The data provide support for the glia-neuron protein transfer hypothesis.

/pdf/evidence-for-the-glia-neuron-protein-transfer-hypothesis-4n6rii4hco.pdf

Evidence for the glia-neuron protein transfer hypothesis from intracellular perfusion studies of squid giant axons.

Large changes in the opacity of the unstained mouse neurohypophysis follow membrane potential changes known to trigger the release of peptide hormones. These intrinsic optical signals, arising in neurosecretory terminals, reflect variations in light scattering and depend upon both the frequency of stimulation and [Ca2+]o. Their magnitude is decreased in the presence of Ca2+ antagonists and by the replacement of H2O in the medium by D2O. These observations suggest a correspondence between the intrinsic optical changes and secretory activity in these nerve terminals.

/pdf/large-and-rapid-changes-in-light-scattering-accompany-1p0y6uepxz.pdf

Harold Gainer

Papers

Studies on bursting pacemaker potential activity in molluscan neurons. III. Effects of hormones.

Neurophysin Biosynthesis: Conversion of a Putative Precursor During Axonal Transport

Biosynthesis of Vasopressin, Oxytocin, and Neurophysins: Isolation and Characterization of Two Common Precursors (Propressophysin and Prooxyphysin)

Evidence for the glia-neuron protein transfer hypothesis from intracellular perfusion studies of squid giant axons.

Large and rapid changes in light scattering accompany secretion by nerve terminals in the mammalian neurohypophysis.