Amyloid Tau link

[corybroo]

Medical Express has an article about a recently found link between amyloid and tau leading to Alzheimer's

https://medicalxpress.com/news/2019-06-alzheimer-link-idd-brain-decline.html

Alzheimer's missing link ID'd, answering what tips brain's decline

 

Years before symptoms of Alzheimer's disease appear, two kinds of damaging proteins silently collect in the brain: amyloid beta and tau. Clumps of amyloid accumulate first, but tau is particularly noxious. Wherever tangles of the tau protein appear, brain tissue dies, triggering the confusion and memory loss that are hallmarks of Alzheimer's.

… the link between the two proteins may lie in the brain's immune cells that hem in clumps of amyloid. If the immune cells falter, amyloid clumps, or plaques, injure nearby neurons and create a toxic environment that accelerates the formation and spread of tau tangles…

 

Powering up microglia might slow the spread of tau tangles and forestall cognitive decline.

 

The last line might be a little confusing.  I found references to CR down regulating microglia and yet other articles suggesting that CR can reduce amyloid.  I hope to learn a lot more before incorporating any changes.

Cory

 

 

[Ron Put]

It appears that inflammation and insulin signalling have much to do with it. And it's not related just to Alzheimer's, but to other neurological diseases as well.

Here is another link on the same topic:

https://www.heighpubs.org/hjc/aac-aid1010.php

"... 

Based on clinical observations, the individuals with treatment of Epidemiological studies were chronically maintained on anti-inflammatory or antioxidant drugs relevant other disease conditions had lower risks for developing cognitive impairment and AD [34]. The hypothesis was approved by various other studies which shows the decrease of NFTs [35,36], tau phosphorylation [37], neurobehavioral (memory) deficits [38], Aβ42 burden [39,40], synaptic degeneration [41-43], and mitochondrial dysfunction [44]. Various anti-oxidants and anti-inflammatory agents that have provided neuroprotection for AD are curcumin [40], alpha-lipoic acid [45-47], Vitamin E [48,49], resveratrol [50], phytonutrients [51], cyclooxygenase 2 inhibitors [52], Ginkgo [53], and melatonin [54]. ...

Studies have found that the major role for a tau hyperphosphorylation which leads to deformation of tau proteins, can be attributed to (i) central disruption of insulin signaling by insulin receptor or (ii) insulin receptor substrate (IRS) 2 gene deletions, (iii) following intracerebral streptozotocine injections (Figure 4) [55]. Therefore, an insulin supplement could improve the cognition and brain energy metabolism in people with mild cognitive impairment or early AD. Further, studies have found that insulin administration enhances clearance of Aβ-42, decreases activity of kinases that promote tau hyperphosphorylation, and enhances signaling through pathways needed for synaptic plasticity [55-58]. ...

In another mechanism, the inhibition of hyperphosphorylation could produce an avoidable condition for the formation of the neurofibrillary tangles. Studies have shown that the glycogen synthase kinase-3 (GSK-3) protein has a prominent function in the stimulation of the hyperphosphorylation of tau proteins. W. Noble and K. Duff presented [59] an in vivo study with transgenic mice overexpressing mutant human tau. The mice were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. ..."

[Dean Pomerleau]

Ron Put quote a study that found (my emphasis):

23 hours ago, Ron Put said:

Various anti-oxidants and anti-inflammatory agents that have provided neuroprotection for AD are curcumin [40], alpha-lipoic acid [45-47], Vitamin E [48,49], resveratrol [50], phytonutrients [51], cyclooxygenase 2 inhibitors [52], Ginkgo [53], and melatonin [54].

All of the bolded agents thought to be protective against Alzheimer's disease have also been shown to boost brown adipose tissue. Coincidence? 🙂

Ron also quoted:

23 hours ago, Ron Put said:

Studies have found that the major role for a tau hyperphosphorylation which leads to deformation of tau proteins [which are implicated in Alzheimer's disease - DP].

And:

23 hours ago, Ron Put said:

Studies have shown that the glycogen synthase kinase-3 (GSK-3) protein has a prominent function in the stimulation of the hyperphosphorylation of tau proteins.

So GSK-3 is bad because it triggers the hyperphosphorylation of tau proteins which seem to result in the tau tangles implicated in AD.

Guess what natural intervention seems to deactivate GSK-3? Cold exposure [1] via this pathway:

Cold -> norepinephrine -> beta-adrenergic stimulation -> PKA -> reduced GSK-3

--Dean

-----------

[1] Sci Rep. 2018 Feb 22;8(1):3469. doi: 10.1038/s41598-018-21795-y. 

GSK3 is a negative regulator of the thermogenic program in brown adipocytes.

Markussen LK(1), Winther S(1), Wicksteed B(2), Hansen JB(3).

Brown adipose tissue is a promising therapeutic target in metabolic disorders due to its ability to dissipate energy and improve systemic insulin sensitivity and glucose homeostasis. β-Adrenergic stimulation of brown adipocytes leads to an increase in oxygen consumption and induction of a thermogenic gene program that includes uncoupling protein 1 (Ucp1) and fibroblast growth factor 21 (Fgf21). In kinase inhibitor screens, we have identified glycogen synthase kinase 3 (GSK3) as a negative regulator of basal and β-adrenergically stimulated Fgf21 expression in cultured brown adipocytes. In addition, inhibition of GSK3 also caused increased Ucp1 expression and oxygen consumption. β-Adrenergic stimulation triggered an inhibitory phosphorylation of GSK3 in a protein kinase A (PKA)-dependent manner. Mechanistically, inhibition of GSK3 activated the mitogen activated protein kinase (MAPK) kinase 3/6-p38 MAPK-activating transcription factor 2 signaling module. In summary, our data describe GSK3 as a novel negative regulator of β-adrenergic signaling in brown adipocytes. DOI: 10.1038/s41598-018-21795-y PMCID: PMC5823915 PMID: 29472592

[Ron Put]

Haha, not so fast, Dean :)

I understand that many lab results indicate that cold may be beneficial in humans, temporarily (the effects appear to diminish with prolonged exposure, as far as I remember). I am also aware that some poor mice are kept at 4ºC, but I think most humans would either die, or be very, very unhappy if they are kept naked at such cold temperatures.

I also believe that if cold exposure was so dramatically beneficial, we would see some population-wide longevity differences, and to my knowledge, there are none (the opposite may be true).

As to dementia, see for example this: https://www.alzheimers.net/5-25-16-drop-in-body-temperature-linked-to-dementia/

Drop in Body Temperature Linked to Dementia

It is normal for people to experience a drop in body temperature with age, but a new study has found that drops in temperature can lead to more than just a chill. A study from Canada found that by increasing body temperature, they could slow the production of beta-amyloid and improve the memory in mice.

“We know that the incidence of Alzheimer’s is low before age 65, but doubles every five to six years afterward. We also know that metabolism and body temperature decrease as people get older. We therefore tested the hypothesis that the changes in the body’s thermoregulation that occur with age amplify the main manifestations of Alzheimer’s and that a vicious circle can even set in because the disease expresses itself in certain areas of the brain involved in temperature regulation.”

“If our conclusions are confirmed, it would be a relatively easy therapeutic option to implement because body temperature can be increased through physical activity, diet, drugs or simply by increasing the ambient temperature....”

Edited June 25, 2019 by Ron Put

[TomBAvoider]

Ron Put, that's a fascinating link. It sort of turns the whole temperature thing on its head. I always thought low body temperature was desirable as it was a sign of lower systemic inflammation. This seems to be a whole new wrinkle on it. 

In this connection it's worth remembering the role of HSP (Heat Shock Proteins) in cold exposure (despite the "heat" name). What is interesting is that another way of generating HSP is through very high temperature exposure - and indeed there appear to be benefits to regular sauna use. A variation of the sauna ritual is practiced in Finland and parts of Russia, where a very hot sauna is followed by an ice bath or a naked-in-the-snow and beatings with twigs - seems you'd generate HSPs from both ends as it were. 

But this thing with temperature you dug up is a real head scratcher. 

[Dean Pomerleau]

First off - I need to correct something I said yesterday in this post above. I said 6 of the 8 anti-oxidant/anti-inflammatory agents that protect again Alzheimer's disease also boost BAT. It is actually 7 of 8, since Vitamin E was added to the list of interventions that boost BAT (see this post from earlier today). I've corrected the post above.

Now a few corrections to Ron's latest post.

Ron wrote:

Quote

I understand that many lab results indicate that cold may be beneficial in humans, temporarily (the effects appear to diminish with prolonged exposure, as far as I remember). 

I challenge you to back up that recollection with actual evidence. I never seen any such evidence of attenuating benefits, despite rather extensive reading on the subject.

Speaking of (not) reading carefully, Ron wrote:

Quote

I also believe that if cold exposure was so dramatically beneficial, we would see some population-wide longevity differences, and to my knowledge, there are none (the opposite may be true).

Why do you keep bringing this up? I've addressed your misunderstanding repeatedly on the cold exposure thread (here and here).

And in a stunning example of more lack of careful reading/research/thinking, Ron wrote:

Quote

As to dementia, see for example this: https://www.alzheimers.net/5-25-16-drop-in-body-temperature-linked-to-dementia/

Drop in Body Temperature Linked to Dementia

It is normal for people to experience a drop in body temperature with age, but a new study has found that drops in temperature can lead to more than just a chill. A study from Canada found that by increasing body temperature, they could slow the production of beta-amyloid and improve the memory in mice.

First off, your link points to an article that is quoting another article in the UK Daily Mirror, a real trustworthy news source :-).

But more to the point, did you ever consider for a moment that this article may actually be evidence of the exact opposite of the conclusion you (and the writer) appear to draw from it?

Namely, that the body temperature drop in aged people and mice may be due to loss of brown adipose tissue with age, and that this loss may be casually responsible (at least in part) for the onset of dementia? Or put another way, did it occur to you that chronic cold exposure improves one's ability to maintain one's body temperature, thereby overcoming the age-associated drop that you and the writer appear to be worried about? Or that simply turning up the thermostat in the late stages of AD to reduce beta-amyloid formation may be a case of too little, too late? 

You probably didn't. But fortunately the Canadian research team of the original article on which your story is based did.

Here is a follow-up study by these same authors from April of this year [1], using the same AD-prone strain of mice used in the study your story obliquely references.

Rather than warming up aged animals to ameliorate the late stage symptoms of AD in these AD-prone mice, they subjected middle-aged mice of this strain to 4h of cold exposure (40F or 4C - ouch!) five days a week for four weeks, and compared them to similar mice house at regular room temperature.

Guess what. Chronic cold exposure completed prevented the harmful tau phosphorylation that occurred in the control mice when both groups were subject to a cold challenge.

In other words, cold exposure boosts BAT in these mice, which allows them to maintain their body temperature better, thereby preventing the phosphorylation to tau proteins implicated in the onset of Alzheimer's disease.

The researchers conclude:

Quote

These results suggest that improving thermogenesis could exert a therapeutic effect in AD. 

Your basic mistake Ron was to equate cold exposure with lower body temperature. Cold exposure (and the brown adipose tissue it induces) actually enables warm-blooded animals (including humans) to thermoregulate more effectively and avoid the age-related drop in body temperature (and loss of BAT) that may be (part of) the cause of Alzheimer's disease.

Thanks for making me look into this further. It's striking how many good things cold exposure and BAT does for the body.

--Dean

------------------------

[1] Mol Metab. 2019 Apr;22:110-120. doi: 10.1016/j.molmet.2019.01.008. Epub 2019 Jan 26.

Repeated cold exposures protect a mouse model of Alzheimer's disease against cold-induced tau phosphorylation.

Tournissac M(1), Bourassa P(1), Martinez-Cano RD(2), Vu TM(2), Hébert SS(3), Planel E(3), Calon F(4). 

OBJECTIVE: Old age is associated with a rise in the incidence of Alzheimer's disease (AD) but also with thermoregulatory deficits. Indicative of a link between the two, hypothermia induces tau hyperphosphorylation. The 3xTg-AD mouse model not only develops tau and amyloid pathologies in the brain but also metabolic and thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals, and its stimulation counteracts metabolic deficits in rodents and humans. We thus investigated whether BAT stimulation impedes AD neuropathology. METHODS: 15-month-old 3xTg-AD mice were subjected to repeated short cold exposures (RSCE), consisting of 4-hour sessions of cold exposure (4 °C), five times per week for four weeks, compared to animals kept at housing temperature. RESULTS: First, we confirmed that 3xTg-AD RSCE-trained mice exhibited BAT thermogenesis and improved glucose tolerance. RSCE-trained mice were completely resistant to tau hyperphosphorylation in the hippocampus induced by a 24-hour cold challenge. Finally, RSCE increased plasma levels of fibroblast growth factor 21 (FGF21), a batokine, which inversely correlated with hippocampal tau phosphorylation. CONCLUSIONS: Overall, BAT stimulation through RSCE improved metabolic deficits and completely blocked cold-induced tau hyperphosphorylation in the 3xTg-AD mouse model of AD neuropathology. These results suggest that improving thermogenesis could exert a therapeutic effect in AD.

DOI: 10.1016/j.molmet.2019.01.008

PMCID: PMC6437631

PMID: 30770297

 

[TomBAvoider]

Yes, but the interesting thing to me is that regardless of the reason why the body temperature drops, the low temp itself seems to be problematic. Maybe having low BAT is responsible, or metabolism or whatnot, and more BAT would prevent temp drops, and therefore CE raising BAT would be a positive as it would allow the body to raise temperature. It still flies in the face of what used to be commonly accepted around here - that having a low body temperature is overall a good thing. I certainly have lower body temp than average and have had this all my life (but particularly since being on CR), but whereas before I took that as a biomarker with a value in my favor, now looks it might be a value not in my favor (at least as far as beta amyloid). That said, I have no other risk factors for Alz save one - neither ApoB, nor diabetes, nor family history, nor high BP - the one exception is high LDL (for which I'm taking a statin), so I don't know how worried I should be about my body temp.  

Also, standard disclaimer which should ALWAYS be put out when linking to such studies: THE STUDY WAS IN MICE. It might, or might not be replicated in humans, but so far it's important to note that it's in MICE.

[Dean Pomerleau]

Tom,

37 minutes ago, TomBAvoider said:

Maybe having low BAT is responsible, or metabolism or whatnot, and more BAT would prevent temp drops, and therefore CE raising BAT would be a positive as it would allow the body to raise temperature.

That seems to be exactly what the authors are suggesting.

38 minutes ago, TomBAvoider said:

It [i.e. having low body temperature may be deleterious - DP] still flies in the face of what used to be commonly accepted around here - that having a low body temperature is overall a good thing. 

Low body temperature and low BAT can certainly be a side effect of CR, especially if practiced to extreme and without accompanying it with cold exposure. But I don't know that anyone has claimed low body temperature per se is a good thing, particularly when it comes to brain health. 

It may not be low body temperature per se is bad when it comes to brain health either. It may be that low body temperature is (sometimes) a marker for impaired thermoregulation, and it is something about the thermogenic pathway itself that is beneficial for brain health.

A good candidate is norepinephrine. Cold exposure stimulates norepinephrine releases both peripherally and from the structure called the locus coeruleus in the brain [1] at least IN RATS! :-). And loss of signalling by norepinephrine and other catecholamines (via adrenergic receptors) appears to be implicated in the early stages of Alzheimer's disease [2]. But it could be something else on the thermogenesis pathway that boosts brain health. Recall for example from this post that cold exposure triggers neurogenesis in the hippocampus (likely also as a result of norepinephrine signalling).

But whatever the exact mechanism, cold exposure appears protective against  some of the hallmarks of Alzheimer's disease, at least in a RODENT MODEL.

--Dean

-------------

[1] Psychopharmacologia. 1969;16(1):1-4.

Effect of chronic cold stress on catecholamine levels in rat brain.

Bhagat B.

Acute stress of various types (foot shock, exposure to cold, etc.) has been shown to reduce the endogenous content of norepinephrine in the brain. On the contrary, the present study indicates that chronic stress produced by exposing rats to cold for 6 h a day for twenty days induced elevated level of endogenous catecholamines in the brain. Also, there was increase in initial accumulation of H3-norepinephrine and increase in turn-over rate of norepinephrine in the brain. It seems that repeated exposure to cold may have induced adaptive changes in physiologic system resulting in acceleration of brain norepinephrine turnover.

PMID: 5359324

--------------

[2] 

Front Neurosci. 2015 Jun 17;9:220. doi: 10.3389/fnins.2015.00220. eCollection
2015.

Noradrenergic dysfunction in Alzheimer's disease.

Gannon M(1), Che P(1), Chen Y(1), Jiao K(2), Roberson ED(3), Wang Q(1).


The brain noradrenergic system supplies the neurotransmitter norepinephrine
throughout the brain via widespread efferent projections, and plays a pivotal
role in modulating cognitive activities in the cortex. Profound noradrenergic
degeneration in Alzheimer's disease (AD) patients has been observed for decades, 
with recent research suggesting that the locus coeruleus (where noradrenergic
neurons are mainly located) is a predominant site where AD-related pathology
begins. Mounting evidence indicates that the loss of noradrenergic innervation
greatly exacerbates AD pathogenesis and progression, although the precise roles
of noradrenergic components in AD pathogenesis remain unclear. The aim of this
review is to summarize current findings on noradrenergic dysfunction in AD, as
well as to point out deficiencies in our knowledge where more research is needed.

DOI: 10.3389/fnins.2015.00220 
PMCID: PMC4469831
PMID: 26136654 

[TomBAvoider]

As always in biology things are way more complicated than we think at first blush. Thank you, Dean, for your valuable addition to this, as about the only thing that really scares me more than death is dementia. I see no point in prolonging life if I'm demented - the one pleasure in life that is consistent for me, is intellectual stimulation/activity. Accordingly, I've kept a sharp eye on markers and predictors of brain health - as you remember, Dean, we went through a whole slew of genetic markers from 23 and me a few years ago, and as I recall both of us were very fortunate in that respect (i.e. no genetic predispositions to dementia, protective variants). As I mentioned, my one bad marker is high LDL, and this was one of the primary reasons for why I finally broke down and went on a statin (and managed to drive my LDL into the low 70's on 10mg of atorvastatin) - I'm even thinking of taking another statin in addition (this time hydrophilic - rosuvastatin 5mg) to drive my LDL below 50 as that seems even more CVD protective (and CVD and brain health are intimately connected). I've looked at all other known factors, sleep, diet, exercise, drugs - and I seem to be doing everything right, so this temperature thing was a nasty surprise. In view of that, I'm thinking of taking measures to increase my BAT, although to be frank I find CE somewhat a tough proposition (much, much tougher than CR!). 

[Dean Pomerleau]

3 minutes ago, TomBAvoider said:

I'm thinking of taking measures to increase my BAT,... 

I'm heartened to hear that. You've been a tough nut to crack :-). 

 

7 minutes ago, TomBAvoider said:

... although to be frank I find CE somewhat a tough proposition (much, much tougher than CR!)

Start slow. It's not bad at all once you get used to it! 

--Dean 

[mccoy]

9 hours ago, TomBAvoider said:

I find CE somewhat a tough proposition (much, much tougher than CR!). 

Like Dean says, slow progression here is the key. Once you are mentally convinced, you'll be able to overcome the initial resistance to CE.

Some possible strategies: starting doing short cold showers in the summer, where municipial water is not cold at all, and go on with the progressive natural decrease of temperature.

Or just apply cold water to your whole skin by ablutions, a much milder way. Or a combination of both.

You can progressively adjust the insulation of the clothes you wear and work gradually from fall to winter, and so on. You can progressively adjust your enclosed environment temperature in summer and especially in winter.

Just one caveat: I would avoid sudden exposures like plunging into cold water or going directly into a cold shower, since the norepinephrine surge would cause a sudden surge in BP and heart rate which may be deleterious. 

Edited June 26, 2019 by mccoy