Enhancing Synaptogenesis in Diseases Characterized by Deficiencies in Brain Synapses

The loss of hippocampal and cortical synapses, resulting from impaired synaptogenesis, accelerated synaptic degeneration, or both, is one of the earliest neuropathologic findings in Alzheimer’s Disease and is the finding that best correlates with cognitive symptoms (DeKosky and Scheff, 1990; Terry et al., 1991; Selkoe, 2002). A similar decrease in brain synapses is an early finding in an animal model of AD which overproduces A-beta peptides (Jacobsen et al., 2006), and aggregates of such peptides, applied locally to the brain, can also damage synapses, distort neurites, and decrease the numbers of the dendritic spines which are essential precursors for glutamatergic synapses (Jacobsen et al., 2006; Spires-Jones et al., 2007; Knobloch and Mansuy, 2008). These observations have supported the widely-held view that a treatment that would block the synthesis of A-beta or remove it from the circulation, might – by depleting its levels in brain – slow the loss of synapses in AD and thereby sustain cognitive functions in patients. A generation of creative and diligent researchers has provided us with abundant information about A-beta’s synthesis, fates, and toxic effects, and this information has been used to generate rationally-designed drug candidates for treating the disease. However to date none of these candidates – even ones shown to reduce brain levels of A-beta oligomers and senile plaques – has been successful in sustaining cognition

Strategies for enhancing catecholamine-mediated neurotransmission

Major findings made during this project period included the following observations: changes in tyrosine availability do affect brain dopamine release, as assessed by in vivo microdialysis, but that neuronal feedback mechanisms limit the durations of this effect except when dopaminergic neurotransmission has been deficient; the circulating hormone TRH markedly stimulates brain dopamine release, an effect probably mediated by its diketopiperazine metabolite; the amount of circulating L-dopa which enters the brain is both enhanced by carbohydrate consumption and suppressed by protein intake (both nutritional effects can be damaging, inasmuch as a sudden rush of L-dopa into the brain can facilitate dyskinesias, while the inhibition of brain L-dopa uptake by proteins suppresses its conversion to brain dopamine; an appropriate mixture of dietary proteins and carbohydrates can obviate both effects); serotonin release from superfused hypothalamic slices is a linear function of available tryptophan levels throughout the normal dynamic range; the daily rhythm in plasma melatonin levels is abnormal both in the sudden infant death syndrome and in women with secondary amenorrhea; tyrosine can potentiate the anorectic effects of widely-used sympathomimetic drugs; newly-described COMT inhibitors can enhance brain dopamine release in vivo; and a cell culture system, based on Y-79 (retinoblast) cells, exists in which melatonin reliably suppresses dopamine release

Cytidine and Uridine Increase Striatal CDP-Choline Levels Without Decreasing Acetylcholine Synthesis or Release

SUMMARY Aims: Treatments that increase acetylcholine release from brain slices decrease the synthesis of phosphatidylcholine by, and its levels in, the slices. We examined whether adding cytidine or uridine to the slice medium, which increases the utilization of choline to form phospholipids, also decreases acetylcholine levels and release. Methods: We incubated rat brain slices with or without cytidine or uridine (both 25-400 µM), and with or without choline (20-40 µM), and measured the spontaneous and potassium-evoked release of acetylcholine. Results: Striatal slices stimulated for 2 h released 2650 ± 365 pmol of acetylcholine per mg protein when incubated without choline, or 4600 ± 450 pmol/mg protein acetylcholine when incubated with choline (20 µM). Adding cytidine or uridine (both 25-400 µM) to the media failed to affect acetylcholine release whether or not choline was also added, even though the pyrimidines (400 µM) did enhance choline`s utilization to form CDP-choline by 89 or 61%, respectively. The pyrimidines also had no effect on acetylcholine release from hippocampal and cortical slices. Cytidine or uridine also failed to affect acetylcholine levels in striatal slices, nor choline transport into striatal synaptosomes. Conclusion: These data show that cytidine and uridine can stimulate brain phosphatide synthesis without diminishing acetylcholine synthesis or release

Presynaptic Control of Release of Amine Neurotransmitters by Precursor Levels

The amounts of such aminergic neurotransmitters as serotonin, dopamine, norepinephrine, and acetylcholine that are released into synapses, spontaneously and when the neurons fire, can be affected by the concentrations of their nutrient precursors tryptophan, tyrosine, and dopamine and can thus be influenced by eating 'real' foods or taking the pure precursors. Simple laws can apparently enable the investigator to predict when precursor levels will or will not have such effects

Biochemistry and Pharmacology of Synaptic Transmission

Considers the process of neurotransmission, especially chemicals used in the brain and elsewhere to carry signals from nerve terminals to the structures they innervate. Focuses on monoamine transmitters (acetylcholine; serotonin; dopamine and norepinephrine); also examines amino acid and peptide transmitters and neuromodulators like adenosine. Macromolecules that mediate neurotransmitter synthesis, release, inactivation, and receptor-mediated actions are discussed, as well as factors that regulate their activity and the second-messenger systems they control. Alternate years

Biochemistry and Pharmacology of Synaptic Transmission

Considers the process of neurotransmission, especially chemicals used in the brain and elsewhere to carry signals from nerve terminals to the structures they innervate. Focuses on monoamine transmitters (acetylcholine; serotonin; dopamine and norepinephrine); also examines amino acid and peptide transmitters and neuromodulators like adenosine. Macromolecules that mediate neurotransmitter synthesis, release, inactivation, and receptor-mediated actions are discussed, as well as factors that regulate their activity and the second-messenger systems they control. Alternate years