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CILTEP, Tau Phosphorylation, Impaired Spatial Memory and Alzheimer's Disease

ciltep memory alzheimers camp pka tau forskolin

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#1 Dizzon

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Posted 08 November 2013 - 05:33 PM


Not trying to be sensationalist here. I just started doing some background research on the 'CILTEP stack' and came across this and was hoping someone with a greater understanding of the subject could figure out whether or not any of this has any relavence to the CILTEP stack. As far as I understand it, it seems to be VERY relevant, but as previously stated im not the most learned individual on the forum in this subject. Honestly Im surprised that Im the first one to mention the subject. For the time being, I wouldn't suggest CILTEP to anyone with a familial history of Alzheimer's or anyone with brain health as their priority. Still seems like a tool for certain aspects of memory retention, but definately looks to be a potential double-edged sword.

Basically, the theory states:
CILTEP = increased unchecked cAMP = increased unchecked PKA = increased unchecked tau phosphorylation = impaired spatial memory & early stages of Alzheimer's

Make sure you read the last study, it's probably the most relevant.


Stimulation of hippocampal adenylyl cyclase activity dissociates memory consolidation processes for response and place learning.

Procedural and declarative memory systems are postulated to interact in either a synergistic or a competitive manner, and memory consolidation appears to be a highly critical stage for this process. However, the precise cellular mechanisms subserving these interactions remain unknown. To investigate this issue, 24-h retention performances were examined in mice given post-training intrahippocampal injections of forskolin (FK) aiming at stimulating hippocampal adenylyl cyclases (ACs). The injection was given at different time points over a period of 9 h following acquisition in either an appetitive bar-pressing task or water-maze tasks challenging respectively "response memory" and "place memory." Retention testing (24 h) showed that FK injection altered memory formation only when given within a 3- to 6-h time window after acquisition but yielded opposite memory effects as a function of task demands. Retention of the spatial task was impaired, whereas retention of both the cued-response in the water maze and the rewarded bar-press response were improved. Intrahippocampal injections of FK produced an increase in pCREB immunoreactivity, which was strictly limited to the hippocampus and lasted less than 2 h, suggesting that early effects (0-2 h) of FK-induced cAMP/CREB activation can be distinguished from late effects (3-6 h). These results delineate a consolidation period during which specific cAMP levels in the hippocampus play a crucial role in enhancing memory processes mediated by other brain regions (e.g., dorsal or ventral striatum) while eliminating interference by the formation of hippocampus-dependent memory.


Duration of tau hyperphosphorylation and spatial memory deficit induced by single injection of Forskolin into lateral ventricle of rat

OBJECTIVE: To investigate the duration of tau hyperphosphorylation and spatial memory retentive deficit induced by single injecting with Forskolin, a protein kinase A activator, into lateral ventricle of rats, and the correlation between the two pathological alterations.
METHODS: Forskolin (80 micromol/L, 40 microl) was injected into the lateral ventricle by stereotaxic injection. Tau phosphorylation and spatial memory retention were measured by Western blot/immunocytochemistry and Morris-Water-Maze test, respectively.
RESULTS: The phosphorylation levels of tau at Tau-1, PHF-1, and pS214 epitopes were significantly elevated at 24, 48 and 72 h after single administration of Forskolin (P < 0.05). The most significant elevation was seen at 48 h (P < 0.01) and it tended to recover at 72 h (P < 0.05) after injection. The correlation between the two pathological alterations was positive at PHF-1 site (r = 0.97, P < 0.05), negative at Tau-1 site (r = -0.963, P < 0.05), and not significant at pS214 site (r = 0.705, P > 0.05).
CONCLUSIONS: Forskolin can induce tau hyperphosphorylation and spatial memory retentive deficit within a certain period of time. The level of tau phosphorylation in hippocampus is somehow correlated with the spatial memory deficit in rats.


Protein kinase A phosphorylation of tau-serine 214 reorganizes microtubules and disrupts the endothelial cell barrier.

Intracellular cAMP is compartmentalized to near membrane domains in endothelium, where it strengthens endothelial cell barrier function. Phosphodiesterase 4D4 (PDE4D4) interacts with the spectrin membrane skeleton and prevents cAMP from accessing microtubules. Expression of a dominant-negative PDE4D4 peptide enables cAMP to access microtubules, where it results in phosphorylation of the nonneuronal microtubule-associated protein tau at serine 214. Presently, we sought to determine whether PKA is responsible for tau-Ser214 phosphorylation and furthermore whether PKA phosphorylation of tau-Ser214 is sufficient to reorganize microtubules and induce endothelial cell gaps. In cells expressing the dominant-negative PDE4D4 peptide, forskolin activated transmembrane adenylyl cyclases, increased cAMP, and induced tau-Ser214 phosphorylation that was accompanied by microtubule reorganization. PKA catalytic and regulatory I subunits, but not the regulatory II subunit, coassociated with reorganized microtubules. To determine the functional consequence of tau-Ser214 phosphorylation, wild-type human tau40 and tau40 engineered to possess an alanine point mutation (S214A) were stably expressed in endothelium. In cells expressing the dominant-negative PDE4D4 peptide and tau-S214A, PKA-dependent phosphorylation of both the endogenous and heterologously expressed tau were abolished. Expression of tau-S214A prevented forskolin from depolymerizing microtubules, inducing intercellular gaps, and increasing macromolecular permeability. These findings therefore identify nonneuronal tau as a critical cAMP-responsive microtubule-associated protein that controls microtubule architecture and endothelial cell barrier function.


Human tau may modify glucocorticoids-mediated regulation of cAMP-dependent kinase and phosphorylated cAMP response element binding protein.

Phosphorylation of the cAMP response element binding protein (CREB) by cAMP-dependent kinase (PKA) is critical to memory formation. However, activation of PKA can also increase tau phosphorylation, which may contribute to memory impairment. Therefore, the regulation of PKA may be part of the mechanism by which glucocorticoids (GCs) influence memory. Additionally, the cellular response to GCs may be affected by the presence of human tau. The goal of this paper was to study GCs-mediated regulation of PKA as well as CREB and tau phosphorylation in wild-type HEK293 cells and HEK293 cells stably expressing human tau441 (HEK293/tau441 cells). By using dexamethasone (DEX) as GCs, we found that DEX induced a tau-dependent selective decrease in the level of PKA RIIβ subunit protein. The observed decrease in RIIβ expression was not due to alterations of mRNA levels and was reversed by inhibiting the proteasome with lactacystin. Moreover, the decrease in RIIβ did not diminish the co-localization of the catalytic subunit of PKA with tau and might contribute to the DEX-induced increase in tau phosphorylation at Ser-214. DEX also induced a tau-dependent decrease in CREB phosphorylation that could not be reversed by activating PKA with forskolin. Taken together, these results show that human tau protein may alter the GCs-mediated regulation of PKA activity and CREB phosphorylation.


Phosphorylation of tau in situ: inhibition of calcium-dependent proteolysis.

In this study, the in situ phosphorylation and subsequent calcium-activated proteolysis of tau protein were examined in human neuroblastoma (LA-N-5) cells, which were differentiated into a neuronal phenotype. The phosphorylation of tau was increased by treating the cells with forskolin and rolipram, which elevate cyclic AMP levels, by treating with the phosphatase inhibitor okadaic acid, or by treating with a combination of both treatments. Phosphorylated tau migrated slightly slower on sodium dodecyl sulfate-polyacrylamide gels than tau from untreated cells. Immunostaining with the phosphate-sensitive monoclonal antibody Tau-1 was also decreased in cells treated with okadaic acid, indicating an increase in the phosphorylation of specific Ser-Pro motifs within the molecule. Calcium-dependent, in situ proteolysis of tau protein was induced by treating the cells with the calcium ionophore A23187. Tau protein was proteolyzed to a significantly lesser extent in cells treated with forskolin and rolipram, okadaic acid, or both than in cells in which phosphorylation was not increased. Partially purified tau protein from cells treated with a combination of forskolin, rolipram, and okadaic acid was also more resistant to proteolysis by calpain in vitro compared with tau isolated from control cells. These data suggest a possible role for phosphorylation in the regulation of tau metabolism and in pathological conditions in which the balance between protein kinases and phosphatases is disrupted.


Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain.

Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and other tauopathies and is believed to lead to neurodegeneration in this family of diseases. Here we show that infusion of forskolin, a specific cAMP-dependent protein kinase A (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by severalfold and concurrently enhanced the phosphorylation of tau at Ser-214, Ser-198, Ser-199, and or Ser-202 (Tau-1 site) and Ser-396 and or Ser-404 (PHF-1 site), which are among the major abnormally hyperphosphorylated sites seen in AD. PKA activation positively correlated to the extent of tau phosphorylation at these sites. Infusion of forskolin together with PKA inhibitor or glycogen synthase kinase-3 (GSK-3) inhibitor revealed that the phosphorylation of tau at Ser-214 was catalyzed by PKA and that the phosphorylation at both the Tau-1 and the PHF-1 sites is induced by basal level of GSK-3, because forskolin activated PKA and not GSK-3 and inhibition of the latter inhibited the phosphorylation at Tau-1 and PHF-1 sites. Inhibition of cdc2, cdk5, or MAPK had no significant effect on the forskolin-induced hyperphosphorylation of tau. Forskolin inhibited spatial memory in a dose-dependent manner in the absence but not in the presence of R(p)-adenosine 3',5'-cyclic monophosphorothioate triethyl ammonium salt, a PKA inhibitor. These results demonstrate for the first time that phosphorylation of tau by PKA primes it for phosphorylation by GSK-3 at the Tau-1 and the PHF-1 sites and that an associated loss in spatial memory is inhibited by inhibition of the hyperphosphorylation of tau. These data provide a novel mechanism of the hyperphosphorylation of tau and identify both PKA and GSK-3 as promising therapeutic targets for AD and other tauopathies.


Estradiol attenuates tau hyperphosphorylation induced by upregulation of protein kinase-A.

Protein kinase A (PKA) plays a crucial role in tau hyperphosphorylation, an early event of Alzheimer disease (AD), and 17beta-estradiol replacement in aging women forestalls the onset of AD. However, the role of estradiol in PKA-induced tau hyperphosphorylation is not known. Here, we investigated the effect of 17beta-estradiol on cAMP/PKA activity and the PKA-induced tau hyperphosphorylation in HEK293 cells stably expressing tau441. We found that 17beta-estradiol effectively attenuated forskolin-induced overactivation of PKA and elevation of cAMP, and thus prevented tau from hyperphosphorylation. These data provide the first evidence that 17beta-estradiol can inhibit PKA overactivation and the PKA-induced tau hyperphosphorylation, implying a preventive role of 17beta-estradiol in AD-like tau pathology.


A transitory activation of protein kinase-A induces a sustained tau hyperphosphorylation at multiple sites in N2a cells-imply a new mechanism in Alzheimer pathology.

Overactivation of protein kinase in the end stage of Alzheimer's disease brain has not been established. The purpose of the present study was to explore the possible mechanism for protein kinases in leading to Alzheimer-like tau hyperphosphorylation. We found that incubation of N2a/tau441 with forskolin, a specific activator of cAMP-dependent protein kinase (PKA), induced an increased phosphorylation level of tau at both PKA and non-PKA sites in a dose- and time-dependent manner, and the hyperphosphorylation of tau was positively correlated with the elevation of PKA activity. When the cells were transitorily incubated with forskolin, a temporary activation of PKA with a sustained and almost equally graded tau hyperphosphorylation at some non-PKA sites was observed. In either case, the activity of glycogen synthase kinase-3 (GSK-3) was not changed. It is suggested that only transitory activation of PKA in early stage of Alzheimer disease may result in a sustained tau hyperphosphorylation at multiple sites, implying a new mechanism to Alzheimer-like tau hyperphosphorylation.


Edited by Dizzon, 08 November 2013 - 06:14 PM.

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#2 abelard lindsay

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Posted 08 November 2013 - 10:56 PM

One thing to keep in mind is they did these experiments with special tau441 cells which are genetically engineered to be hyper-susceptible to tau aggregation so as to serve as a disease model for testing potential treatments for Alzheimers. Just about anything is going to eventually cause Alzheimer's in those cells. They are just using these cells as a laboratory to experiment with the natural process of tau aggregation that these cells exhibit. Also, Forskolin is one of the most widely used experimental tools in microbiology. There are over 20000 studies in pubmed in which it is mentioned. It's the go-to substance whenever an experimenter wants to increase cAMP levels in cells. They were using it to manipulate cAMP levels in these hyper-susceptible cells and not to determine if it was the cause of Alzheimer's.

There haven't been any other studies with N2a/Tau441 that I can find on pubmed but here's an example with a SH-SY5Y cell modified to be tau441 over-expressing.

http://www.ncbi.nlm....pubmed/22351109

For this reason, dependable in vitro and in vivo models that reflect tau hyperphosphorylation in human diseases are needed. In this study, we generated and validated an in vitro model appropriate to test potential curative and preventive compound effects on tau phosphorylation. For this purpose, a stably transfected SH-SY5Y cell line was constructed over-expressing mutant human tau441 (SH-SY5Y-TMHT441). Analyses of expression levels and tau phosphorylation status in untreated cells confirmed relevance to human diseases.


Also, interestingly enough, several studies suggest Rolipram (PDE4 inhibitor) is therapeutic for Alzheimer's Disease! In fact, its effects are quite astonishing. See below!

http://www.ncbi.nlm....pubmed/23173065

Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD.


http://www.ncbi.nlm....pubmed/19805389

Synapse loss is strongly correlated with cognitive impairment in Alzheimer's disease (AD). We have previously reported the loss of dendritic spines and the presence of dystrophic neurites in both the hippocampi of transgenic mice overexpressing amyloid precursor protein (APP) and in the human brain affected with AD. In the studies reported here we have asked whether the acute alterations in dendritic spines induced by Abeta, as well as the chronic loss of spine density seen in hAPP transgenic mice, are reversible by treatments that restore the cAMP/PKA/CREB signaling pathway or proteasome function to control levels. The results show that both rolipram and TAT-HA-Uch-L1 restore spine density to near control conditions, even in elderly mice. The results suggest that changes in dendritic structure and function that occur after Abeta elevation are reversible even after long periods of time, and that one could envision therapeutic approaches to AD based on this restoration that could work independently of therapies aimed at lowering Abeta levels in the brain


http://www.ncbi.nlm....pubmed/15578094

Persistent improvement in synaptic and cognitive functions in an Alzheimermouse model after rolipram treatment.
Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O.
Source
The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.
Abstract

Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels.


All these positive studies make me wonder why there aren't any patient advocacy groups pushing for trials with Rolipram given intravenously so as to avoid emesis. It's amazing that the effects lasted for two months after treatment!

Edited by abelard lindsay, 08 November 2013 - 11:36 PM.

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#3 Dizzon

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Posted 16 November 2013 - 03:53 PM

Good to hear from you Abelard and a good point r.e. Tau441 studies and Rolipram. However I hope we can both agree that something that's potentially net beneficial for a brain with Alzheimer's doesn't mean its beneficial for the normal brain (Cannabis for example.) For the time being I'm willing to gloss over the Tau 441 studies (4th, 7th and 8th studies), the transgenic mouse study (3rd study), and the in situ study with rolipram (5th Study), to focus on the 1st, 2nd and 6th studies, all of which show forskolin causing long-term impaired spatial memory and hippocampal tau phosphorylation (initial stages of Alzheimer's) in normal rats. The same studies that also, by the way, show improvements in other areas of memory similar to what people experience from the CILTEP stack.

Stimulation of hippocampal adenylyl cyclase activity dissociates memory consolidation processes for response and place learning.

Procedural and declarative memory systems are postulated to interact in either a synergistic or a competitive manner, and memory consolidation appears to be a highly critical stage for this process. However, the precise cellular mechanisms subserving these interactions remain unknown. To investigate this issue, 24-h retention performances were examined in mice given post-training intrahippocampal injections of forskolin (FK) aiming at stimulating hippocampal adenylyl cyclases (ACs). The injection was given at different time points over a period of 9 h following acquisition in either an appetitive bar-pressing task or water-maze tasks challenging respectively "response memory" and "place memory." Retention testing (24 h) showed that FK injection altered memory formation only when given within a 3- to 6-h time window after acquisition but yielded opposite memory effects as a function of task demands. Retention of the spatial task was impaired, whereas retention of both the cued-response in the water maze and the rewarded bar-press response were improved. Intrahippocampal injections of FK produced an increase in pCREB immunoreactivity, which was strictly limited to the hippocampus and lasted less than 2 h, suggesting that early effects (0-2 h) of FK-induced cAMP/CREB activation can be distinguished from late effects (3-6 h). These results delineate a consolidation period during which specific cAMP levels in the hippocampus play a crucial role in enhancing memory processes mediated by other brain regions (e.g., dorsal or ventral striatum) while eliminating interference by the formation of hippocampus-dependent memory.


Duration of tau hyperphosphorylation and spatial memory deficit induced by single injection of Forskolin into lateral ventricle of rat

OBJECTIVE: To investigate the duration of tau hyperphosphorylation and spatial memory retentive deficit induced by single injecting with Forskolin, a protein kinase A activator, into lateral ventricle of rats, and the correlation between the two pathological alterations.
METHODS: Forskolin (80 micromol/L, 40 microl) was injected into the lateral ventricle by stereotaxic injection. Tau phosphorylation and spatial memory retention were measured by Western blot/immunocytochemistry and Morris-Water-Maze test, respectively.
RESULTS: The phosphorylation levels of tau at Tau-1, PHF-1, and pS214 epitopes were significantly elevated at 24, 48 and 72 h after single administration of Forskolin (P < 0.05). The most significant elevation was seen at 48 h (P < 0.01) and it tended to recover at 72 h (P < 0.05) after injection. The correlation between the two pathological alterations was positive at PHF-1 site (r = 0.97, P < 0.05), negative at Tau-1 site (r = -0.963, P < 0.05), and not significant at pS214 site (r = 0.705, P > 0.05).
CONCLUSIONS: Forskolin can induce tau hyperphosphorylation and spatial memory retentive deficit within a certain period of time. The level of tau phosphorylation in hippocampus is somehow correlated with the spatial memory deficit in rats.


Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain.

Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and other tauopathies and is believed to lead to neurodegeneration in this family of diseases. Here we show that infusion of forskolin, a specific cAMP-dependent protein kinase A (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by severalfold and concurrently enhanced the phosphorylation of tau at Ser-214, Ser-198, Ser-199, and or Ser-202 (Tau-1 site) and Ser-396 and or Ser-404 (PHF-1 site), which are among the major abnormally hyperphosphorylated sites seen in AD. PKA activation positively correlated to the extent of tau phosphorylation at these sites. Infusion of forskolin together with PKA inhibitor or glycogen synthase kinase-3 (GSK-3) inhibitor revealed that the phosphorylation of tau at Ser-214 was catalyzed by PKA and that the phosphorylation at both the Tau-1 and the PHF-1 sites is induced by basal level of GSK-3, because forskolin activated PKA and not GSK-3 and inhibition of the latter inhibited the phosphorylation at Tau-1 and PHF-1 sites. Inhibition of cdc2, cdk5, or MAPK had no significant effect on the forskolin-induced hyperphosphorylation of tau. Forskolin inhibited spatial memory in a dose-dependent manner in the absence but not in the presence of R(p)-adenosine 3',5'-cyclic monophosphorothioate triethyl ammonium salt, a PKA inhibitor. These results demonstrate for the first time that phosphorylation of tau by PKA primes it for phosphorylation by GSK-3 at the Tau-1 and the PHF-1 sites and that an associated loss in spatial memory is inhibited by inhibition of the hyperphosphorylation of tau. These data provide a novel mechanism of the hyperphosphorylation of tau and identify both PKA and GSK-3 as promising therapeutic targets for AD and other tauopathies.

Anyone?

Edited by Dizzon, 16 November 2013 - 04:50 PM.

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#4 High_Probability

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Posted 10 May 2017 - 09:36 PM

Good to hear from you Abelard and a good point r.e. Tau441 studies and Rolipram. However I hope we can both agree that something that's potentially net beneficial for a brain with Alzheimer's doesn't mean its beneficial for the normal brain (Cannabis for example.) For the time being I'm willing to gloss over the Tau 441 studies (4th, 7th and 8th studies), the transgenic mouse study (3rd study), and the in situ study with rolipram (5th Study), to focus on the 1st, 2nd and 6th studies, all of which show forskolin causing long-term impaired spatial memory and hippocampal tau phosphorylation (initial stages of Alzheimer's) in normal rats. The same studies that also, by the way, show improvements in other areas of memory similar to what people experience from the CILTEP stack.
 

Stimulation of hippocampal adenylyl cyclase activity dissociates memory consolidation processes for response and place learning.

Procedural and declarative memory systems are postulated to interact in either a synergistic or a competitive manner, and memory consolidation appears to be a highly critical stage for this process. However, the precise cellular mechanisms subserving these interactions remain unknown. To investigate this issue, 24-h retention performances were examined in mice given post-training intrahippocampal injections of forskolin (FK) aiming at stimulating hippocampal adenylyl cyclases (ACs). The injection was given at different time points over a period of 9 h following acquisition in either an appetitive bar-pressing task or water-maze tasks challenging respectively "response memory" and "place memory." Retention testing (24 h) showed that FK injection altered memory formation only when given within a 3- to 6-h time window after acquisition but yielded opposite memory effects as a function of task demands. Retention of the spatial task was impaired, whereas retention of both the cued-response in the water maze and the rewarded bar-press response were improved. Intrahippocampal injections of FK produced an increase in pCREB immunoreactivity, which was strictly limited to the hippocampus and lasted less than 2 h, suggesting that early effects (0-2 h) of FK-induced cAMP/CREB activation can be distinguished from late effects (3-6 h). These results delineate a consolidation period during which specific cAMP levels in the hippocampus play a crucial role in enhancing memory processes mediated by other brain regions (e.g., dorsal or ventral striatum) while eliminating interference by the formation of hippocampus-dependent memory.


Duration of tau hyperphosphorylation and spatial memory deficit induced by single injection of Forskolin into lateral ventricle of rat

OBJECTIVE: To investigate the duration of tau hyperphosphorylation and spatial memory retentive deficit induced by single injecting with Forskolin, a protein kinase A activator, into lateral ventricle of rats, and the correlation between the two pathological alterations.
METHODS: Forskolin (80 micromol/L, 40 microl) was injected into the lateral ventricle by stereotaxic injection. Tau phosphorylation and spatial memory retention were measured by Western blot/immunocytochemistry and Morris-Water-Maze test, respectively.
RESULTS: The phosphorylation levels of tau at Tau-1, PHF-1, and pS214 epitopes were significantly elevated at 24, 48 and 72 h after single administration of Forskolin (P < 0.05). The most significant elevation was seen at 48 h (P < 0.01) and it tended to recover at 72 h (P < 0.05) after injection. The correlation between the two pathological alterations was positive at PHF-1 site (r = 0.97, P < 0.05), negative at Tau-1 site (r = -0.963, P < 0.05), and not significant at pS214 site (r = 0.705, P > 0.05).
CONCLUSIONS: Forskolin can induce tau hyperphosphorylation and spatial memory retentive deficit within a certain period of time. The level of tau phosphorylation in hippocampus is somehow correlated with the spatial memory deficit in rats.


Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain.

Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and other tauopathies and is believed to lead to neurodegeneration in this family of diseases. Here we show that infusion of forskolin, a specific cAMP-dependent protein kinase A (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by severalfold and concurrently enhanced the phosphorylation of tau at Ser-214, Ser-198, Ser-199, and or Ser-202 (Tau-1 site) and Ser-396 and or Ser-404 (PHF-1 site), which are among the major abnormally hyperphosphorylated sites seen in AD. PKA activation positively correlated to the extent of tau phosphorylation at these sites. Infusion of forskolin together with PKA inhibitor or glycogen synthase kinase-3 (GSK-3) inhibitor revealed that the phosphorylation of tau at Ser-214 was catalyzed by PKA and that the phosphorylation at both the Tau-1 and the PHF-1 sites is induced by basal level of GSK-3, because forskolin activated PKA and not GSK-3 and inhibition of the latter inhibited the phosphorylation at Tau-1 and PHF-1 sites. Inhibition of cdc2, cdk5, or MAPK had no significant effect on the forskolin-induced hyperphosphorylation of tau. Forskolin inhibited spatial memory in a dose-dependent manner in the absence but not in the presence of R(p)-adenosine 3',5'-cyclic monophosphorothioate triethyl ammonium salt, a PKA inhibitor. These results demonstrate for the first time that phosphorylation of tau by PKA primes it for phosphorylation by GSK-3 at the Tau-1 and the PHF-1 sites and that an associated loss in spatial memory is inhibited by inhibition of the hyperphosphorylation of tau. These data provide a novel mechanism of the hyperphosphorylation of tau and identify both PKA and GSK-3 as promising therapeutic targets for AD and other tauopathies.

Anyone?

 

 

I realize that this is a super old post but can anyone provide insight into Dizzon's concerns regarding the 1st, 2nd and 6th studies?  Are you out there Abelard?


Edited by High_Probability, 10 May 2017 - 09:47 PM.


#5 High_Probability

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Posted 02 November 2017 - 10:03 PM

Seriously?  I mean I know Ciltep is old news and not as sexy as it used to be (on this forum at least) but can someone please speak to the above studies?


Edited by High_Probability, 02 November 2017 - 10:04 PM.


#6 gamesguru

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Posted 03 November 2017 - 08:27 PM

although it should come as no surprise glutamate stuff promotes alzheimer's, this is nothing for the average user to worry about.  Unless you're old with a strong family history, don't obsess over glutamate or cyclic amp.  These things conspire together (tau, beta amyloids, glutamate, camp) it's true and that's why mematine found some use.. but generally you don't notice symptoms until the proverbial straw that broke the camel's back, typically after age 55

 

I would recommend glutamate supplements only in short bursts.  They can provide an immense boost in learning and productivity, but will wear you out long term.  Instead reserve it for rare occasions and use the rest of the week to balance out your chemistry with curcumin, luteolin, or some such glutamate release inhibitor.

 

Not even sure ciltep can hold its own against newer, more potent stacks like black tea, ginkgo and/or rhodiola, royal jelly and methylene blue



#7 Kinesis

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Posted 04 November 2017 - 03:58 AM

GG would this extend to racetams? Correct me if I’m wrong but I thought they worked in part through glutaminergic mechanisms, e.g as mild ampakines. I’ve been under the impression that they were generally good for long term brain health and in older people, but the point you raise could call that into question, unless I misunderstand.

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#8 gamesguru

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Posted 06 November 2017 - 09:04 PM

in part is a good phrase to use here.  They are only weakly glutamatergic (excluding nefi, colu, faso, phenyl), and the association between alzheimer's and glutamate itself is weak.

 

And so we have a problem with inference.  That causes this, so one assumes if some other thing causes that, it must also cause this.  But in your body we have tissue not logic gates.. signaling pathways rarely exist a one to one correspondence, it's more like a 0.7 to 1.0 correspondence so after a few steps you lose sight of your target.

 

Quite possible that piracetam, despite its concerns over excitotoxicity, is able to prop up the dying patient with some compensatory PKC/PKI inhibition or simply that the choline significantly contributes to survival of the cytoskeleton.  There are so many possibilities to consider and so little time in a day







Also tagged with one or more of these keywords: ciltep, memory, alzheimers, camp, pka, tau, forskolin

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