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Cyclic GMP and Nitric Oxide Synthase in Aging and Alzheimer’s Disease Presented By : Amin Younis Uniwersytet Medyczny w Łodzi

Introduction:

Introduction cGMP is a widely distributed secondary messenger in the mature brain. The level of cGMP is much higher in the brain compared with the peripheral organs. The final concentration of cGMP in cells depends on the balance of its synthesis via guanylyl cyclase(s) and degradation by PDEs (Phosphodiesterases). Aging is associated with an increase in PDE expression and activity ( decrease in cGMP concentration). In addition, aging is also associated with an enhancement of neuronal NO synthase.

NO/cGMP Pathway:

NO/cGMP Pathway cGMP Synthesis and Degradation

Alterations in Nitric Oxide Synthase Expression and Activity:

Alterations in Nitric Oxide Synthase Expression and Activity NO is produced by NOS enzymes (nNOS, eNOS and iNOS) which use L-arginine as substrate.

Alterations in Nitric Oxide Synthase Expression and Activity:

Alterations in Nitric Oxide Synthase Expression and Activity nNOS: Several findings indicate that NO synthesis is altered in the aged brain in which H igh mRNA expression of the neuronal form of nNOS in several brain regions can be observed. In addition, research shows that during aging there is an enhancement of Ca2+ and calmodulin-dependent nNOS activity in all investigated brain parts with significantly higher value in the cerebellum and hippocampus. nNOS

Alterations in Nitric Oxide Synthase Expression and Activity:

Aged Brain Increased NOS activity Increased NO Alterations in Nitric Oxide Synthase Expression and Activity

Nitric Oxide Alterations Role in Alzheimer Disease:

Nitric Oxide Alterations Role in Alzheimer Disease In the early phase , NO supports the survival of cells through a cGMP dependent mechanism , but in the later phase, NO overproduction may contribute to the apoptotic process by reacting with excess superoxide anions, leading to peroxynitrite production and protein alterations by nitration and nitrosylation , mitochondria failure, and subsequently, neuronal degeneration and cell death.

Nitric Oxide Alterations Role in Alzheimer Disease:

Nitric Oxide Alterations Role in Alzheimer Disease

Nitric Oxide Alterations Role in Alzheimer Disease:

Nitric Oxide Alterations Role in Alzheimer Disease Concentration of an endogenous NOS inhibitor, asymmetrical dimethylarginine (ADMA), in CSF from senescent and AD patients is significantly decreased with age, whereas the arginine concentration was unaltered. All isoforms of NOS are altered in Alzheimer Disease, indicating a critical role for NO in the pathology of A lzheimer disease characterized by loss of neurons and synapses in the hippocampus and cerebral cortex and in certain subcortical regions.

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Administration of PDE inhibitors (IBMX, PDE2 inhibitor) resulted in significantly higher levels of cGMP in all parts of the aged as well as in the adult brains, suggesting that sGC is active in the senescent brain . T here is evidence that the ability of cholinergic neurons in the basal forebrain, inter-neurons in the striatum and hippocampus to synthesize cGMP via the NO-dependent pathway was decreased during aging. cGMP Alterations in Guanylyl Cyclase and cGMP Synthesis

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Aged Brain Decreased sGC Expression and Increased PDE Expression Decreased cGMP Alterations in Guanylyl Cyclase and cGMP Synthesis

NO/cGMP Pathway:

NO/cGMP Pathway

PDEs Inhibitors:

PDEs Inhibitors The underlying mechanisms of cognitive impairment during aging have not been fully understood . But, there is an indication that learning and memory impairment in older animals is a consequence of reduced function of the glutamate/NO/cGMP pathway in the aged brain and probably also alteration in the cholinergic signaling. The increase in PDE expression and activity may lead to more intensive cGMP hydrolysis in the senescent brain.

PDEs Inhibitors:

PDEs Inhibitors PDEs Inhibitors Effect on Object Recognition

Long Term Potentiation:

Long Term Potentiation S imple electrical recordings from glutamate-operated pathways in isolated slices of the hippocampus (a brain region much involved in memory processes ) occur in synapses located in other brain regions concerned with memory, e.g. the cerebral cortex. P ost-synaptic response to a subsequent low/normal frequency stimulation i s greatly enhanced. This enhancement of postsynaptic response lasts for at least several hours, and has been shown to last for weeks .

NO/cGMP Pathway and LTP:

NO/cGMP Pathway and LTP

Summary:

Summary ?

Summary:

In general, based on the above information, it is possible to conclude that new therapeutic strategies for the maintenance of a good cognitive performance in elderly people could be developed on the basis of cGMP metabolism. Selective agents that can enhance cGMP concentration. (i.e. PDEs Inhibitors) Summary LTP Memory Improvement

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