Use of Phosphatide Precursors to Promote Synaptogenesis

Abstract

New brain synapses form when a postsynaptic structure, the dendritic spine, interacts with a presynaptic terminal. Brain synapses and dendritic spines, membrane-rich structures, are depleted in Alzheimer's disease, as are some circulating compounds needed for synthesizing phosphatides, the major constituents of synaptic membranes. Animals given three of these compounds, all nutrients-uridine, the omega-3 polyunsaturated fatty acid docosahexaenoic acid, and choline-develop increased levels of brain phosphatides and of proteins that are concentrated within synaptic membranes (e.g., PSD-95, synapsin-1), improved cognition, and enhanced neurotransmitter release. The nutrients work by increasing the substrate-saturation of low-affinity enzymes that synthesize the phosphatides. Moreover, uridine and its nucleotide metabolites activate brain P2Y receptors, which control neuronal differentiation and synaptic protein synthesis. A preparation containing these compounds is being tested for treating Alzheimer's disease.

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

“…Therefore, increased Urd formation may mediate the positive effects of cytidine diphosphocholine (CDPcholine) on verbal memory in aging humans (Spiers et al 1996 ) . Consequently, CDP-choline and other nutritional components that increase brain Urd levels (Wurtman et al 2000 ) may be important, especially during the early phases of Alzheimer's disease ( Van der Beek and Kamphuis 2008 ;Wurtman et al 2009 ) .…”

Modern Views on the Impact of Long-Chain Polyunsaturated Fatty Acids on the Development of the Child’s Nervous System

“…При этом в отличие от циркулирующей крови, где содержание ДЦПНЖК семейства 6 в 10 раз выше, чем содержание жирных кислот семейства 3, в нервных клет-ках, а также в сетчатой оболочке глаза, напротив, выше концентрация ДГК, и именно ДГК преобладает в невраль-ных синапсах [26,27]. ДГК поступает в клетки мозга как за счет пассивной диффузии, так и за счет активного транспорта специализированными белками [28].…”

Involvement of Nutrients in the Pathogenesis or Management of Alzheimer’s Disease

“…22,23 There are various loci at which such a treatment might work. For example, it could increase the flux of free calcium into stimulated dendrites, activate receptors that control the formation of dendritic spines, increase the synthesis of pre-or post-synaptic proteins, or generate new synaptic membrane, the main constituent of synapses.…”

“…Conversion of the three circulating precursors to phosphatides is mediated by enzymes that have relatively low affinities for these substrates, and thus are unsaturated at the precursor concentrations normally present in the blood and brain. The choline in blood is obtained from various foods or is synthesised in the liver 22 via a pathway that requires methionine and thus is accelerated when vitamins B12, B6 and folic acid are administered. 28 Circulating uridine, in humans, also derives from hepatic synthesis.…”

“…22 Uridine is also present in most foods in the form of RNA; however, there is no satisfactory evidence that this particular potential source of uridine can provide significant quantities of uridine to the circulation (in contrast to the uridine present as uridine monophosphate [UMP] in mothers' milk and infant formulas). 22 As described above, DHA, an essential fatty acid, is obtained from dietary DHA and from the hepatic conversion of alpha-linolenic acid to DHA, a process described as disturbed in AD. 19 Because the enzymes that initiate the conversion of these compounds to PC are unsaturated, their activities are readily enhanced when their substrates are administered.…”