What can be done to fight off Alzheimer’s disease?

Alzheimer's,Neuroscience FAQ, Q&A,Parkinson's,Pyruvate — 12:41 pm

Q&A and FAQ (archived) :: Ongoing Q&A :: Neuroscience Q&A and FAQ

Question
I’ve read on WebMD that there’s no evidence that anything can be done to fight off Alzheimer’s disease. But I also read the opposite opinions. What is yours? – Donna

Answer
Dear Donna,

You probably mean the following conclusion cited by WebMD:

“There is currently no evidence considered to be of even moderate scientific quality supporting the association of any modifiable factor (nutritional supplements, herbal preparations, dietary factors, prescription or nonprescription drugs, social or economic factors, medical conditions, toxins, environmental exposures) with reduced risk of Alzheimer’s disease,” concludes the report, issued by a National Institutes of Health consensus panel on Alzheimer’s prevention.”

I am surprised that they haven’t mentioned exercise, for which, in my humble opinion, a solid body of evidence exists and the caffein research, for which intricate mechanisms are being researched. Also, quite a few harmful influences such as hydrogen peroxide, glutamate, zinc, and copper/cysteine were convincingly reported. I added caffein effects on another neurodegenerative disease, the Parkinson’s but I know of similar studies in Alzheimer’s.

Walking away from dementia

Coffee, tea, and chocolate can help to avoid Parkinson’s disease

Pyruvate protects neurons against A-beta peptides characteristic for Alzheimer’s
Tanya Zilberter

Sweet and sour recipes for the brain 4. “Physiological” concentrations: what and where?

Excitatory GABA,Ketone bodies,Lactate,Methodology,Pyruvate — 6:27 am

Part 2. Energy substrates: too sour?
Part 3. Let the neurons breathe!

What concentrations are physiological and what are not (usually called pharmacological)? The physiological ones  normally refer to the levels of a substance relevant to the naturally occurring, which, logically, for neurons is the milieu they strive in. It is called extracellular fluid (ECF) and is notorious for dramatic differences with not only blood (plasma) but even with the cerebrospinal fluid (CSF).

“Importantly, microdialysis data have shown that both in adult humans and in rats,the basal glucose levels are about 1–2 mM in the ECF of the neocortex and hippocampus [32,33,37,38] compared with 5–7 mM in the blood, whereas concentrations of lactate are about 2–5 mM in the ECF [32,34,39,40] compared with 1–2 mM in the adult blood.” (Zilberter et al., 2010). The authors further stressed the imperative of providing adequate means for energy substrates to be utilized in the artificial milieu, in which brain slices are placed:

“In brain slices, energy deficiency cannot be managed in the same way as in whole-body homeostasis, resulting in higher ES levels in  slices than in vivo. The importance of a proper oxygen supply should be stressed [55], because oxidative phosphorylation is proportional to the presence of O2. Therefore, at an inadequate oxygen level, the efficacy of ES might be negligible. It is not surprising that energy metabolism in slices differs from that occurring in the living brain, and is probably impaired [52–54].”

Khakhalin (2011) wrote in his recent review that effects of ES on GABA action has been shown for “…4-5  mM concentrations of beta-hydroxybutyrate  (Rheims et al. 2009), lactate and pyruvate (Holmgren et al. 2010), and was later confirmed by independent research groups for similar concentrations of pyruvate (Tyzio et al. 2011), and lactate (Ruusuvuori et al. 2010).” He continued arguing whether  the concentrations were  ”physiological ” in the experiments showing equal results in different authors who made, however, different conclusions: Tyzio et al. state that the physiological concentration of pyruvate is 1.6 – the one they measured in plasma.

“This comparison may be not valid, however, as it is well known from microdialysis studies that the extracellular fluid, immediately surrounding neural cells, differs in its composition not only from the blood plasma, but even from the cerebrospinal fluid. In particular, concentration of lactate in the extracellular fluid of rats and humans was found to be 2-5 times higher than in the blood plasma… 4-5 mM concentrations are likely to be physiologically relevant… On the other hand, at these concentrations both lactate and pyruvate induce noticeable changes in GABA- and glutamatergic transmission in developing neural networks. It means that some changes in experimental protocols and related theoretical paradigms may still be necessary.”

Kasischke (2011) in his comment on the article by Ivanov et al., 2011, wrote: “From the very beginning, the authors took great care to ensure both viability and functionality of their preparations.”

“An important implication of this methodological tour de force is that under many previously reported experiments the requirements for viability may been met while the functionality may have been compromised.”

References

 

  1. Zilberter Y, Zilberter T, Bregestovski P. (2010) Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis. Trends Pharmacol Sci., 31(9):394-401
  2. [32,33,3437,38,39,40,52-55]  are cited in Zilberter et al. (2010)
  3. Khakhalin A (May 18, 2011). Questioning the depolarizing effects of GABA during early brain development. J Neurophysiol doi: 0.1152/jn.00293.2011.
  4. Tyzio et al. (2011) and  Ruusuvuori et al. (2010) are cited in Khakhalin ( 2011).
  5. Kasischke K (2011). Lactate fuels the neonatal brain. Frontiers in Neuroenergetics; 3, 4

“Brain metabolism in vitro” and those sour energy substrates

Brain metabolism,Energy Substrates,Excitatory GABA,Glucose,Ketone bodies,Lactate,Pyruvate — Tags: , — 10:31 am

Part 2. Energy substrates: too sour?
Part 3. Let the neurons breathe!
This paper suggests that the developmental switch in the reversal potential for gamma-aminobutyric acid (GABA) is regulated by different energy sources

This paper suggests that the developmental switch in the reversal potential for gamma-aminobutyric acid (GABA) is regulated by different energy sources

An evaluation of our article (1) appeared in the “Faculty of 1000 postpublication peer reviews” the conclusion being:

The findings of Rheims et al. have a potentially major impact on our understanding of GABAergic function during development, bringing back an element of inhibition in developing neuronal networks that appeared to rely entirely on excitatory connections (2).

This article (1) along with the article (3) later became an indirect subject of another evaluation (4) although formally, the evaluation concerned a different paper (5), which has been commended because (the author’s words):

“It settles an important issue related to brain metabolism in vitro and the role of acidification in brain patterns.”

The acidification issue doesn’t seem to be resolved either in 5 nor in 4, so a comment to the evaluation appeared in May 2011,  stating among other things the following:

We showed that inhibition of spontaneous network activity in neonatal hippocampal slices by energy substrates is not correlated with intracellular acidification (7) and that they work altering intrinsic features of energy metabolism namely NAD(P)H and oxygen utilization (8).

Another data challenged in 5 is whether lactate as efficient as an energy substrate: “Lactate is not an efficient replacement for glucose” wrote Dr Ben-Ari and Y. Zilberter in his comment referred to the paper 8 titled “Lactate effectively covers energy demands during neuronal network activity in neonatal hippocampal slices” and the work of Wyss et al. (9) titled “In Vivo Evidence for Lactate as a Neuronal Energy Source”.

References

1. Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y. (2009) J Neurochem.  Aug;110(4):1330-8. Epub 2009 Jun 22. (on Brain Fuels)

2. Scimemi A, Diamond J: 2009. F1000.com/1166168

3. Holmgren CD, Mukhtarov M, Malkov AE, Popova IY, Bregestovski P, Zilberter Y. (2010) J Neurochem. Feb;112(4):900-12. Epub 2009 Nov 24. (on Brain Fuels)

4. Ben-Ari Y: 2011. F1000.com/6913961

5. Ruusuvuori E, Kirilkin I, Pandya N, Kaila K (2010) J Neurosci.  Nov 17; 30(46):15638-42

6. Zilberter Y, Zilberter T, Bregestovski P. (2010) Trends Pharmacol Sci., 31(9):394-401 (on Brain Fuels)

7. Mukhtarov, M., Ivanov, A., Zilberter, Y., and Bregestovski, P. (2011) J Neurochem 116, 316-321

8. Ivanov A, Mukhtarov M, Bregestovski P and Zilberter Y (2011) Front. Neuroenerg. 3:2.

9. Wyss M, Jolivet R, Buck A, Magistretti P, and Weber B. (2011)  J Neuroscience, 31(20):7477-7485

Sweet and sour recipes for the brain. 1. “Sweet slices are fine”?

Applications,Energy Substrates,Glucose,Ketone bodies,Lactate,Pyruvate — 10:32 am

Part 2. Energy substrates: too sour?
Part 3. Let the neurons breathe!

Is glucose the absolutely exclusive fuel for the brain? In popular articles, you might always read that yes, it is.

Meanwhile, in special scientific literature the role of quite a few energy carriers including ketone bodies (mostly beta-hydroxybutirate, BHB), lactate, and pyruvate was unquestioned for decades. Recently, a series of three research reports published in the Journal of Neuroscience (Tyzio et al., 2011, Ruusuvuori et al., 2010 and Kirmse et al., 2010) arrived at the conclusion contradicting to the well known fact about brain energy metabolism in neonates. It seemed indisputable that in the neonatal brain, the use of glucose as an energy substrate is limited due to immaturity of the mechanisms of glucose utilization but the articles in question shed doubts on it. Why is it important to sort out these conflicting research results?

I already wrote about the importance of energy substrates other than glucose for the immature brain and the consequence of ignoring this role in experiments on neonatal brain slices discussing the results of Rheims et al., 2009 and Holmgren et al., 2010.

In 2010, at the meeting of the Society for Neuroscience in San Diego, CA, a poster has been presented announcing in its title: “BHB does not alter GABA signals in neonatal slices: sweet slices are fine, no need to alter conventional ACSF“. Neither poster nor its abstract (Picardo et al., 2010) contained methodical details and they remained unknown until 2011 when an article in the Journal of Neuroscience was published (Tyzio et al., 2011). It became possible to compare the differences in methods, which has been done in due time and published in the Frontiers in Neuroenergetics (Ivanov et al., 2011) — see parts 2-4.

Important is, that Ivanov et al. showed that in immature brain slices, glucose rendered less efficient energy carrier than lactate, BHB, and pyruvate.  Judged by the hallmarks of energy metabolism – oxygen utilization and nicotinamide adenine dinucleotide phosphate or NAD(P)H, neuronal activity robustness was higher in the presence of lactate alone or combined with glucose than with glucose alone. The authors concluded: “We show that in the presence of glucose, lactate is effectively utilized as an energy substrate, causing an  augmentation of oxidative metabolism. Moreover, in the absence of glucose lactate is fully capable of maintaining synaptic function. Therefore, during network activity in neonatal slices, lactate can be  an efficient energy substrate capable of sustaining and enhancing aerobic energy metabolism.”

References

  1. Garcia, A.J., 3rd, Putnam, R.W., and Dean, J.B. (2010). Hyperbaric hyperoxia and normobaric reoxygenation increase excitability and activate oxygen-induced potentiation in CA1 hippocampal neurons. J Appl Physiol 109, 804-819.
  2. Hajos, N., Ellender, T.J., Zemankovics, R., Mann, E.O., Exley, R., Cragg, S.J., Freund, T.F., and Paulsen, O. (2009). Maintaining network activity in submerged hippocampal slices: importance of oxygen supply. Eur J Neurosci 29, 319-327.
  3. Holmgren CD, Mukhtarov M, Malkov AE, Popova IY, Bregestovski P, Zilberter Y (2010) Energy substrate availability as a determinant of neuronal resting potential,GABAsignaling and spontaneous network activity in the neonatal cortex in vitro. J Neurochem 112:900 –912.
  4. Ivanov A, Mukhtarov M, Bregestovski P and Zilberter Y (2011). Lactate effectively covers energy demands during neuronal network activity in neonatal hippocampal slices. Front. Neuroenerg. 3:2.
  5. Kirmse K, Witte OW, Holthoff K. (2010). GABA Depolarizes Immature Neocortical Neurons in the Presence of the Ketone Body β-Hydroxybutyrate. J Neuroscience, 24; 30(47): 16002-16007
  6. Lehninger, A.L. (2005). “Oxydative phosphorylation and photophosphorylation,” in Principles of biochemistry, eds. D.L. Nelson & M.M. Cox. Forth ed: W. H. Freeman), 690-740.
  7. Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y (2009) GABA action in immature neocortical neurons directly depends on the availability of ketone bodies. J Neurochem 110: 1330–1338.
  8. Schurr, A., and Payne, R.S. (2007). Lactate, not pyruvate, is neuronal aerobic glycolysis end product: an in vitro electrophysiological study. Neuroscience 147, 613-619.
  9. Tyzio, R., Allene, C., Nardou, R., Picardo, M.A., Yamamoto, S., Sivakumaran, S., Caiati, M.D., Rheims, S., Minlebaev, M., Milh, M., Ferre, P., Khazipov, R., Romette, J.L., Lorquin, J., Cossart, R., Khalilov, I., Nehlig, A., Cherubini, E., and Ben-Ari, Y. (2011). Depolarizing actions of GABA in immature neurons depend neither on ketone bodies nor on pyruvate. J Neurosci 31, 34-45.

Great Controversies in Neurobiogy

Excitatory GABA,Glucose,Ketone bodies,Methodology,Pyruvate — 9:47 am

“They teach us in our institutes that GABA is excitatory in the neonates, should we still believe it?” (Excitatory GABA scandal?)

There was an interesting development in the Department of Neuroscience of the Brown University who published a provocative recommendation to the Neuro 193E Course under the general title “Great Controversies in Neurobiogy.”

Since 80′s it was becoming a firmly established fact that in immature brain, the reversal potential for GABA receptors was more depolarized, making GABA excitatory and producing a special form of electrical activity named the giant depolarizing potentials, GDP, described by Ben-Ari in hippocampal slices of the immature brain.

“This is something which has been widely described in multiple brain regions by many different labs and is pretty much accepted as fact,” wrote the course’s authors. “However,” continues the chapter, “about a year ago, a couple of papers from the Zilberter’s lab (1, 2) have seriously brought this fact into question.”

The matter is, as multiple prior studies showed [as reviewed in 3, BF], the immature brain “is not very good at metabolizing glucose” due to the immaturity of glycolytic mechanisms and instead it relies on brain fuels alternative to glucose, such as ketones, lactate, and/or pyruvate.

“They noted that almost all papers published using brain slices use artificial cerebro-spinal fluid (ACSF) made with pleny of glucose, but no ketones. Which means that any immature slices cut and maintained in this media will likely be metabolically compromised.”

“They show quite convincingly that adding ketone bodies to ACSF used for immature slices actually makes GABA reversal potential more negative, similar to an adult neuron. Thus they suggest that the depolarizing actin of GABA during early development is an experimental artifact of metabolically-compromised brain slices,” concluded the author.

Source: Dept. of Neuroscience, Brown University. Course Neuro 193E. Last edited by Carlos Aizenman-Stern on Aug 24, 2010 15:34

References

  1. GABA Action in Immature Neocortical Neurons Directly Depends on the Availability of Ketone Bodies. Rheims S, Holmgren CD, Chazal G,Mulder J, Harkany T, Zilberter T, Zilberter Y. J Neurochem 2009;110(4):1330–13382.
  2. Energy Substrate Availability as a Determinant of Neuronal Resting Potential, GABA Signaling and Spontaneous Network Activity in the Neonatal Cortex In Vitro. Holmgren CD,MukhtarovM,Malkov AE, Popova IY, Bregestovski P, Zilberter Y. J Neurochem 2010;112(4):900–912
  3. Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis. Trends Pharmacol Sci. 2010 Sep;31(9):394-401. Epub 2010 Jul 14. Zilberter Y, Zilberter T, Bregestovski P.

Energy substrates and neuroprotection: what does what

Epilepsy,Glucose,Ketone bodies,Lactate,Neuroprotectors,Pyruvate — Tags: — 6:05 am

A few interesting articles about glucose, lactate, and pyruvate
and their neuroprotective functions.

J Neurochem. 2010 Feb 15
Chronic in vitro ketosis is neuroprotective but not anticonvulsant.
Marina Samoilova, Michael Weisspapir, Peter Abdelmalik, Alexander A
Velumian, Peter L Carlen

Chronic in vitro treatment with a ketone body, D-beta-hydroxybutyrate
(DbetaHB), protected the cultures against chronic hypoglycemia,
oxygen-glucose deprivation and NMDA-induced excitotoxicity, but failed
to suppress intrinsic and induced seizure-like activity, indicating
improved neuroprotection is not directly translated into seizure
control. However, chronic in vitro ketosis abolished hippocampal
network hyperexcitability following a metabolic insult, hypoxia,
demonstrating for the first time a direct link between metabolic
resistance and better control of excessive, synchronous, abnormal
electrical activity.

Neuroscience. 2007 Jun 7
Lactate, not pyruvate, is neuronal aerobic glycolysis end product: An
in vitro electrophysiological study. A Schurr, R S Payne

We hypothesized that, in the brain, both aerobic and anaerobic
glycolysis terminate with the formation of lactate from pyruvate by the
enzyme lactate dehydrogenase (LDH). If this hypothesis is correct,
lactate must be the mitochondrial substrate for oxidative energy
metabolism via its oxidation to pyruvate, plausibly by a mitochondrial
LDH

Neurosci Res. 2004 Dec;50 (4):467-74
Glycolysis regulates the induction of lactate utilization for synaptic
potentials after hypoxia in the granule cell of guinea pig hippocampus.
Toshihiro Takata, Bo Yang, Takashi Sakurai, Yasuhiro Okada, Koichi
Yokono

Population spikes are not maintained with lactate following hypoxia in
10 mM glucose medium, but are maintained at their original levels with
lactate after exposure to hypoxia in lower concentration (5 mM) of
glucose.

Neurosci Res. 2003 Jul ;46 (3):333-7
Effects of lactate/pyruvate on synaptic plasticity in the hippocampal
dentate gyrus.
Bo Yang, Takashi Sakurai, Toshihiro Takata, Koichi Yokono

Replacement of glucose with lactate and pyruvate maintained population
spikes after transient depression, and supported a similar degree of
paired-pulse facilitation. These results indicate that monocarboxylates
could serve as sufficient substrates LTP but with less efficiency than
glucose.

Neuroscience. 2007 Jun 7
Lactate, not pyruvate, is neuronal aerobic glycolysis end product: An
in vitro electrophysiological study.A Schurr, R S Payne

 

We hypothesized that, in the brain, both aerobic and anaerobic
glycolysis terminate with the formation of lactate from pyruvate by the
enzyme lactate dehydrogenase (LDH). If this hypothesis is correct,
lactate must be the mitochondrial substrate for oxidative energy
metabolism via its oxidation to pyruvate, plausibly by a mitochondrial
LDH


Neurosci Res. 2004 Dec 50 (4):467-74
Glycolysis regulates the induction of lactate utilization for synaptic
potentials after hypoxia in the granule cell of guinea pig
hippocampus.Toshihiro Takata, Bo Yang, Takashi Sakurai, Yasuhiro Okada,
Koichi Yokono

 

Population spikes are not maintained with lactate following hypoxia in
10 mM glucose medium, but are maintained at their original levels with
lactate after exposure to hypoxia in lower concentration (5 mM) of
glucose.

 

Not only ketone bodies: on neuroprotective effects of energy substrates

Energy Substrates,Epilepsy,Excitatory GABA,Lactate,Neuroprotectors,Pyruvate — Tags: , , , , , , , , , — 7:16 am

In the previous post On the mechanisms of brain protection by ketones, I described how a shortage of ketones caused pathological changes in brain cells in brain slices (in vitro, 1) and in whole animals (in vivo, 2) resulting in abnormal (excitatory) behavior of GABA, the principal brain chemical helping to resist hyperactivity. (more…)

Pyruvate protects neurons against A-beta peptides characteristic for Alzheimer’s

Neuroprotectors,Pyruvate — Tags: , , , , , — 8:26 am

Pyruvate is one of major energy carriers in the brain, it is shown to be protective against damaging consequences of neurotoxins, such as hydrogen peroxide, glutamate, zinc, and copper/cysteine (1). Pyruvate plus another energy substrate, malate, in addition to standard glucose concentrations, protects embryonic neurons in the brain region such as hippocampus and cortex against glutamate excitotoxicity (2). These pyruvate and malate effects promoting neuronal survival were preferential over over glucose suggested that glucose-derived pyruvate from glucose may be limited in neurons studied in vitro, especially under conditions of elevated energy demands. neurons.

Supplementation of glucose-containing culture media with energy substrates, pyruvate plus malate (P/M), protected rat primary neurons from degeneration and death caused by A-beta peptides characteristic for Alzheimer’s disease (3).

Source: Pyruvate Protection Against -Amyloid-Induced Neuronal Death: Role of Mitochondrial Redox State. Gema Alvarez, Milagros Ramos, Francisca Ruiz, Jorgina Satrustegui, and Elena Bogonez. Journal of Neuroscience Research 73:260-269 (2003)

Citations from the source:

  1. Eimerl and Schramm 1995; Desagher et al., 1997; Ruiz et al., 1998; Sheline et al., 2000; Wang and Cynader, 2001
  2. Ruiz et al., 1998
  3. Alvarez et al., 2003

Additional information

Ivanov et al. (2011) supplemented glucose with 5 mM pyruvate in ACSF. Pyruvate induced a strong increase in the NAD(P)H oxidation phase and oxygen consumption during neuronal stimulation suggesting that pyruvate enhances aerobic energy metabolism and synaptic integrity. Effects of pyruvate in the same concentration on normalization of on GABA reversal potential first shown by Y. Zilberter’s group (Holmgren et al., 2010) has been confirmed by Tyzio et al. (2011) although the authors, for some reason measuring pyruvate contents in the blood, not ECF, arrived at the conclusion that the concentration was non-physiological  (see discussion here)

References

  • Ivanov A, Mukhtarov M, Bregestovski P and Zilberter Y (2011). Lactate effectively covers energy demands during neuronal network activity in neonatal hippocampal slices. Front. Neuroenerg. 3:2.
  • Tyzio R, Allene C, Nardou R, Picardo M, Yamamoto S, Sivakumaran S, Caiati MD, Rheims S, Minlebaev M, Milh M, Ferre P, Khazipov R, Romette J-L, Lorquin J, Cossart R, Khalilov I, Nehlig A, Cherubini E, Ben-Ari Y. (2011) Depolarizing Actions of GABA in Immature Neurons Depend Neither on Ketone Bodies Nor on Pyruvate. pp 34-45.

Exceptional energy demands of the brain and energy substrates

Energy Homeostasis,Ketone bodies,Lactate,Pyruvate — Tags: , , — 7:59 am
  • In addition to glucose, other substrates must be considered along with fuel interactions, metabolic challenges, and cerebral maturation. (1)
  • Ketone bodies are major metabolic fuels of the brain of the suckling rat under normal conditions. (2)
  • Ketone bodies can represent about 30–70% of the total energy metabolism balance of the immature rat brain.(3)
  • Lactate is an important metabolic substrate for the brain…and plays a crucial role in brain development… Once the onset of suckling takes place, however, ketone bodies become the major fuel for brain development.(4)
  • 70% of the cerebral metabolic requirements were met by lactate in animals aged 6 days. At 15 days of age, glucose, 3-hydroxybutyrate, and lactate supply 58%, 19%, and 23% of the brain’s fuel requirement, respectively.(5)

Sources:
1. Prins, M. L. (2008) J Cereb Blood Flow Metab, 28, 1-16.
2. Hawkins, R. A., Williamson, D. H. and Krebs, H. A. (1971) Biochem J, 122, 13-18.
3. Nehlig, A. (2004) Prostaglandins Leukot Essent Fatty Acids, 70, 265-275.
4. Medina, J. M. and Tabernero, A. (2005) J Neurosci Res, 79, 2-10.
5. Dombrowski, G. J., Jr., Swiatek, K. R. and Chao, K. L. (1989) Neurochem Res, 14, 667-675.
To leave a comment or question click here