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.

INTRACELLULAR injection techniques have traditionally been used in neurobiology to characterize the morphology of neurons (STRETTON & KRAVITZ. 1968; PITTMAN e t al.. 1972; %HUBERT et al.. 1971). Recently, intracellular injection of various radioactively labelled precursors has been used both for morphological study, and for biochemical analysis of neurotransmitter (EISENSTADT e t al., 1973) and macromolecular synthesis (%HUBERT et al., 1971 ; KREUTZHERG & %-HUBERT. 1973). We have injected labelled amino acids into the somata of neurons in an attempt at determining which of the proteins synthesized in the soma are selectively transported into the axonal processes. In preliminary experiments, we found that only a small percentage of the injected amino acid was incorporated into protein into the cell, thus precluding the study of selective protein transport. In this paper, we report ( I ) that the procedure of intracellular injection itself does not disturb the mechanisms of protein synthesis and (2) that extracellular amino acids, as opposed to amino acids directly injected into the cell, are preferentially utilized for protein synthesis. Identified neurons in ganglia dissected from the molluscs Orala lactea (GAINER, 1972) and Aplpsia cal$wnica (FRAZIER et al.. 1967) were used in these experiments. The various procedures for dissection, and the composition of the physiological salines used have been reported elsewhere (GAINER. 1971, 1972). For intracellular injection it was necessary to remove the connective tissue sheath which covered the neurons. One mCi of ~-[4,5,-'H(N)]leucine (31.9 Ci/m-mole) was lyophilized to dryness, dissolved in 5 pl of distilled water, and stored in a petri dish under silicone oil at -70°C). Intracellular injection of this labelled precursor (and other substances) was done by the technique described by EISENSTADT et al. (1973). Briefly, double-barrelled glass micropipettes were used, one barrel allowed recording of the membrane potential of the neuron by conventional techniques while the other was filled with 1-3 nl of the solution to be injected under visual control by application of pressure. The complete injection took less than one min. and only transiently altered the electrical properties of the neuronal membrane (Fig. I. upper inset). Following successful injection there was no evidence of any significant changes in membrane potential. spike frequency and amplitude. and membrane electrical resistance (not illustrated). Since these parameters are relatively sensitive to memhrane changes, we interpret their stability following injection as evidence that the procedure had not damaged the cell membrane. Damaged neurons. not fulfilling the above electrophysiological criteria after injection. were discarded. With sufficient practice the average percentage of successful injections was better than 70%. The amount of labelled amino acid injected into the cell was estimated by drawing a given vol. of the concentrated ['Hlleucine solution into the injection barrel, marking the meniscus of the solution in the capillary, and ejecting this solution directly into a scintillation vial for counting. Given the specific activity of the [3H]leucine (31.9 Ci/mmole), and the efficiency of counting of the 'H-channel

Preferential incorporation of extracellular amino acids into neuronal proteins.

An approach to the study of intracellular proteins related to the excitability of the squid giant axon.

Ultrastructural immunolocalization of rat oxytocin-neurophysin in transgenic mice expressing the rat oxytocin gene.

Bursting pacemaker potential activity in a normally silent neuron.

1. 1. Protein turnover rates were studied in three identified neurons, R2, R14 and R15, in the abdominal ganglion of Aplysia. 2. 2. In the bursting pacemaker neuron, R15, about 25 per cent of the de novo protein synthesis of the cell is directed towards producing a rapidly turning over class of small (about 12,000 daltons) proteins. 3. 3. Application of dopamine to the incubation medium causes a selective decrease in synthesis of this protein class, whereas increases in the K+ ion concentration of the medium causes a selective increase. 4. 4. This significance of these modulation effects and their relationship to turnover is discussed.

Harold Gainer

Papers

Preferential incorporation of extracellular amino acids into neuronal proteins.

An approach to the study of intracellular proteins related to the excitability of the squid giant axon.

Ultrastructural immunolocalization of rat oxytocin-neurophysin in transgenic mice expressing the rat oxytocin gene.

Bursting pacemaker potential activity in a normally silent neuron.

Selective modulation and turnover of proteins in identified neurons of Aplysia.