8 replies to this topic

[SearchHorizon]

I am asking for feedback on the question I posed in the title (what you think of it).

 

Here is a bit of background. I have been trying to help my 82-year old mother fight dementia. I have observed that phosphatidyl serine (PS)  administration has a real effect on her memory (in particular, converting short-term memory into a long-term one). Having checked pubmed, as it turns out, there are human studies that definitively show PS's beneficial effects on cognition.

 

I then came across some studies that indicate d-serine strongly promotes neurogenesis (at least in mice). In humans, d-serine is synthesized from l-serine, via a racemase. Then, I started thinking that it seems rather coincidental that both PS and d-serine help/promote nerve cells. Perhaps, the reason that both d-serine and PS help neurons is its relationship to l-serine?

 

If age-related dementia is generally caused by shortage of l-serine (whose production declines with age), it would explain what I observed in my mom (and what I read), with respect to d-serine and PS.

 

It appears that l-serine's biosynthesis depends on an intermediate from glycolysis. What is striking to me about this fact is that my mom has high blood sugar level (which is common with age-related dementia). It would make sense that high blood sugar level is indicative of inefficient or defective glycolysis, which I think could leads to l-serine shortage. 

 

So, is it possible/likely that age-related dementia can be traced back to l-serine shortage? Thoughts anyone?

 

P.S. I have read about cases of children/babies with serine deficiency, but have not been able to find studies regarding age-related  l-serine deficiency.

 

 

[gamesguru]

It is unlikely such a complex disease can be explained by one metric. Neurotrophins, hormones, peptides, and misc gene expressions are also at play.


“We hypothesized that a combination of multiple nutritional additives may be able to provide neuroprotection. We demonstrate herein that dietary supplementation with a mixture of ALA, ALCAR, GPC, DHA, and PS reduced reactive oxygen species in normal mice by 57% and prevented the increase in reactive oxygen species normally observed in mice lacking murine ApoE when maintained on a vitamin-free, iron-enriched, oxidative-challenge diet. We further demonstrate that supplementation with these agents prevented the marked cognitive decline otherwise observed in normal mice maintained on this challenge diet. These findings add to the growing body of research indicating that key dietary supplementation may delay the progression of age-related cognitive decline.”

[SearchHorizon]

It is unlikely such a complex disease can be explained by one metric. Neurotrophins, hormones, peptides, and misc gene expressions are also at play.

 

Neurotropins, peptides, and misc gene expressions all might be involved, but I think they are likely to be part of the overall picture surrounding a failed, upstream mechanism. In other words, there is likely to be a common, upstream cause.

 

GIven that dementia tend to occur in older folks, dementia is likely related to the mechanism behind aging. Latest research studies point to DNA damage (whether that is at telomere or at other parts) as a major contributor to biological aging, so it is natural to look for failed DNA function. A failed DNA function, of course, implies reduced, or inability to produce some biological substrate.

 

Just an opinion, of course ...

Edited by SearchHorizon, 20 May 2016 - 06:55 AM.

[gamesguru]

Okay look, unless you take a holistic approach, the benefits of manipulating serine will be disguised in white noise.

If you're low in vitamin c,d,e, magnesium, selenium, even lithium has a role to play in maintaining normal health... and you think you can bypass the whole issue with one particular metric, serine, and put everything in order, I think you're gonna soon be bitterly disappointed.

[APBT]

See these:

https://www.youtube.com/watch?v=7jWi6WQQ9wo

http://www.bbc.com/n...health-35350450

[gamesguru]

It's a similar misfolding as seen in alzheimer's and mad cow, rogue proteins precipitating chain reactions. mad cow is much more "runaway" or "chain reaction" than alzheimer, which can be slowed by supplementing normal proteins or inhibiting critical enzymes or pathways, or it can be accelerated by things like anesthesia, stroke, or low antioxidant diets. BMAA appears to be a rogue form of l-serine, that's why they compete in the "tangling process".

Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain
Paul Alan Cox, David A. Davis, Deborah C. Mash, James S. Metcalf, Sandra Anne Banack (2016)

Neurofibrillary tangles (NFT) and β-amyloid plaques are the neurological hallmarks of both Alzheimer's disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer's, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments, we found that chronic dietary exposure to a cyanobacterial toxin present in the traditional Chamorro diet, β-N-methylamino-l-alanine (BMAA), triggers the formation of both NFT and β-amyloid deposits similar in structure and density to those found in brain tissues of Chamorros who died with ALS/PDC. Vervets (Chlorocebus sabaeus) fed for 140 days with BMAA-dosed fruit developed NFT and sparse β-amyloid deposits in the brain. Co-administration of the dietary amino acid l-serine with l-BMAA significantly reduced the density of NFT. These findings indicate that while chronic exposure to the environmental toxin BMAA can trigger neurodegeneration in vulnerable individuals, increasing the amount of l-serine in the diet can reduce the risk.

The Non-Protein Amino Acid BMAA Is Misincorporated into Human Proteins in Place of l-Serine Causing Protein Misfolding and Aggregation
Rachael Anne Dunlop, Paul Alan Cox, Sandra Anne Banack, Kenneth John Rodgers (2013)

Mechanisms of protein misfolding are of increasing interest in the aetiology of neurodegenerative diseases characterized by protein aggregation and tangles including Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Lewy Body Dementia (LBD), and Progressive Supranuclear Palsy (PSP). Some forms of neurodegenerative illness are associated with mutations in genes which control assembly of disease related proteins. For example, the mouse sticky mutation sti, which results in undetected mischarging of tRNAAla with serine resulting in the substitution of serine for alanine in proteins causes cerebellar Purkinje cell loss and ataxia in laboratory animals. Replacement of serine 422 with glutamic acid in tau increases the propensity of tau aggregation associated with neurodegeneration. However, the possibility that environmental factors can trigger abnormal folding in proteins remains relatively unexplored. We here report that a non-protein amino acid, β-N-methylamino-L-alanine (BMAA), can be misincorporated in place of l-serine into human proteins. We also report that this misincorporation can be inhibited by l-serine. Misincorporation of BMAA into human neuroproteins may shed light on putative associations between human exposure to BMAA produced by cyanobacteria and an increased incidence of ALS.

 

here's a good review, might be worth skimming, highlighting how multiple mechanisms converge and how the strongest link determines the magnitude of the chain (therefore it supports my original assertion that l-serine will not attack all causes of dementia):

The multiple mechanisms of amyloid deposition

[thedevinroy]

I think there is a likely downstream commonality... But I am one to agree that the theories are far and wide on dementia and its causes. The end result is always the same - a slowly dying brain.

So, you're not all wrong. Lowered phospholipid synthesis over time will create damaged neurons from inflammation. That damage spreads somehow via the aforementioned changes in transcription factors.

Why don't you check out the genes associated with the type of dementia your mother has, determine the function of the proteins, and then see if there is a correlation.

https://www.alzheime...ads&fileID=1759


Sent from my iPhone using Tapatalk

[gamesguru]

another key player in amyloid deposition may be microglial overactivation. that's typical response to HSV-1 in the CNS. it may be counterproductive to strongly turn off or compromise microglial (immune cells), but rather we may seek to modulate over- and hypo-activity. GABA astrocytes regulate the microglia, and i have a feeling this may explain some of cannabis' memory impairment (it specifically destroys GABA astrocytes). other flavonoids also regulate them, that combined with their antioxidant profiles may have them finding application as anti-dementia agents.

Microglia activation in the brain as inflammatory biomarker of Alzheimer's disease neuropathology and clinical dementia.
Xiang Z1, Haroutunian V, Ho L, Purohit D, Pasinetti GM. (2006)

The role of microglia-mediated inflammation in the progression of Alzheimer's disease (AD) neuropathology remains unclear. In this study, postmortem brain sections from AD and control cases were subjected to Human Leukocyte Antigen (HLA)-DR immunohistochemistry to examine microglia activation in the progression of AD assessed by pre-mortem clinical dementia rating (CDR) and postmortem pathological manifestations of neuritic plaque (NP) and neurofibrillary tangle (NT) according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). In both gray and white matter of the entorhinal cortex (EC) and HLA-DR immunostaining increased with the progression of CDR or CERAD NP, and to a lesser degree with CERAD NT. Between CDR stages HLA-DR significance was found in moderate (CDR 2) to severe dementia (CDR 5) where as between CERAD NP stages staining increased significantly from NP 0 (no plaque) to NP 1 (sparse plaques), suggesting increased microglia activation begins with amyloid NP deposition. In the hippocampus, a significant increase in microglia immunostaining was found in the pyramidal cell layer of CA1 as early as CDR 1, and in the upper molecular layer of the dentate gyrus in CDR 0.5. This increase continues with the progression of CDR and reaches maximum in CDR 5. When assessed by CERAD NP stages however, a significant increase in microglia immunostaining was found only in mid-to-late stages (NP 3) and reduced staining was seen in NP 5. These results suggest that microglia activation increases with the progression of AD, with the increase varying depending on the involved brain region.

 

Microglia Function in Alzheimer’s Disease
Egle Solito1 and Magdalena Sastre (2012)

Contrary to early views, we now know that systemic inflammatory/immune responses transmit to the brain. The microglia, the resident “macrophages” of the brain’s innate immune system, are most responsive, and increasing evidence suggests that they enter a hyper-reactive state in neurodegenerative conditions and aging. As sustained over-production of microglial pro-inflammatory mediators is neurotoxic, this raises great concern that systemic inflammation (that also escalates with aging) exacerbates or possibly triggers, neurological diseases (Alzheimer’s, prion, motoneuron disease). It is known that inflammation has an essential role in the progression of Alzheimer’s disease (AD), since amyloid-β (Aβ) is able to activate microglia, initiating an inflammatory response, which could have different consequences for neuronal survival. On one hand, microglia may delay the progression of AD by contributing to the clearance of Aβ, since they phagocyte Aβ and release enzymes responsible for Aβ degradation. Microglia also secrete growth factors and anti-inflammatory cytokines, which are neuroprotective. In addition, microglia removal of damaged cells is a very important step in the restoration of the normal brain environment, as if left such cells can become potent inflammatory stimuli, resulting in yet further tissue damage. On the other hand, as we age microglia become steadily less efficient at these processes, tending to become over-activated in response to stimulation and instigating too potent a reaction, which may cause neuronal damage in its own right. Therefore, it is critical to understand the state of activation of microglia in different AD stages to be able to determine the effect of potential anti-inflammatory therapies. We discuss here recent evidence supporting both the beneficial or detrimental performance of microglia in AD, and the attempt to find molecules/biomarkers for early diagnosis or therapeutic interventions.

 

Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD.
Han J1, Kesner P, Metna-Laurent M, Duan T (2012)

Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo.

 

Regulation of innate immune responses in the brain
Serge Rivest (2009)

Microglial cells are the main innate immune cells of the complex cellular structure of the brain. These cells respond quickly to pathogens and injury, accumulate in regions of degeneration and produce a wide variety of pro-inflammatory molecules. These observations have resulted in active debate regarding the exact role of microglial cells in the brain and whether they have beneficial or detrimental functions. Careful targeting of these cells could have therapeutic benefits for several types of trauma and disease specific to the central nervous system. This Review discusses the molecular details underlying the innate immune response in the brain during infection, injury and disease.

 

Policing the Police: Astrocytes Modulate Microglial Activation
Andy Y. Shih, Herman B. Fernandes (2008)

Within hours after an acute brain injury
such as a stroke, the brain mounts an in-
flammatory response involving activation
of local microglia/astrocytes and infiltra-
tion of macrophages from circulation.
The inflammatory process is a double-
edged sword, because increased produc-
tion of reactive oxygen and nitrogen spe-
cies (ROS/RNS) by immune cells can
cause secondary damage up to weeks after
injury, yet the subsequent remodeling of
brain tissue requires the efficient con-
tainment and removal of dead tissue.
The recent paper by Min et al. (2006) in
The Journal of Neuroscience
furthers our
understanding of how the brain intrin-
sically
controls inflammation during in-
jury, providing important clues on how
damage caused by inflammation can be
minimized  while  beneficial  effects  are
maximized.
Microglia are resident immune cells
of the brain and an important compo-
nent of the brain inflammatory re-
sponse.

Astrocytes are GABAergic cells that modulate microglial activity.
Lee M1, Schwab C, McGeer PL. (2011)

GABA is assumed to function in brain only as an inhibitory neurotransmitter. Here we report a much broader CNS role. We show that human astrocytes are GABAergic cells, and that human microglia are GABAceptive cells. We show that in adult human brain tissue, astrocytes immunostain for the GABA synthesizing enzyme GAD 67, the GABA metabolizing enzyme GABA-T and the GABA(A) and GABA(B) receptors. The intensity of staining is comparable or greater to that observed for known inhibitory neurons. We show that cultured human astrocytes strongly express the mRNA and protein for GAD 67, as well as GABA-T, and the GABA(A) and GABA(B) receptors. We further show that cultured human microglia express the mRNA and protein for GABA-T, in addition to the GABA(A) and GABA(B) receptors characterizing them as GABAceptive cells. We demonstrate that GABA suppresses the reactive response of both astrocytes and microglia to the inflammatory stimulants lipopolysaccharide (LPS) and interferon-γ by inhibiting induction of inflammatory pathways mediated by NFκB and P38 MAP kinase. This results in a reduced release of the inflammatory cytokines TNFα and IL-6 and an attenuation of conditioned medium neurotoxicity toward neuroblastoma SH-SY5Y cells. These inhibitory reactions are partially mimicked by the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen, indicating that GABA can stimulate both types of receptors in astrocytes as well as microglia. We conclude that the antiinflammatory actions of GABA offer new therapeutic opportunities since agonists should enhance the effectiveness of other antiinflammatory agents that operate through non-GABA pathways.

Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression
Kavon Rezai-Zadeh†, Jared Ehrhart† (2008)
Background
It is well known that most neurodegenerative diseases are associated with microglia-mediated inflammation. Our previous research demonstrates that the CD40 signaling is critically involved in microglia-related immune responses in the brain. For example, it is well known that the activation of the signal transducer and activator of transcription (STAT) signaling pathway plays a central role in interferon-gamma (IFN-γ)-induced microglial CD40 expression. We and others have previously reported that microglial CD40 expression is significantly induced by IFN-γ and amyloid-β (Aβ) peptide. Recent studies have shown that certain flavonoids possess anti-inflammatory and neuroprotective properties distinct from their well-known anti-oxidant effects. In particular, flavonoids, apigenin and luteolin have been found to be effective CD40 immunomodulators.
Methods
Cultured microglia, both N9 and primary derived lines, were treated with flavonoids in the presence of IFN-γ and/or CD40 ligation to assess any anti-inflammatory effects and/or mechanisms. CD40 expression on microglia was analyzed by fluorescence activated cell sorting (FACS). Anti-inflammatory effects and mechanisms were confirmed by ELISA for interlekin-6 (IL-6) and TNF-α, lactate dehydrogenase (LDH) assay, and STAT1 Western blotting.
Results
Apigenin and luteolin concentration-dependently suppressed IFN-γ-induced CD40 expression. Apigenin and luteolin also suppressed microglial TNF-α and IL-6 production stimulated by IFN-gamma challenge in the presence of CD40 ligation. In addition, apigenin and luteolin markedly inhibited IFN-γ-induced phosphorylation of STAT1 with little impact on cell survival.
Conclusion
Our findings provide further support for apigenin and luteolin's anti-inflammatory effects and suggest that these flavonoids may have neuroprotective/disease-modifying properties in various neurodegenerative disorders, including Alzheimer's disease (AD).

[kurdishfella]

diseases are usually not caused by one single nutrient. deficiency in protein can make lack of enzymes to break down injectables.