Alzheimer’s

[Michael Scally MD]

Abuznait AH, Qosa H, Busnena BA, El Sayed KA, Kaddoumi A. Olive-Oil-Derived Oleocanthal Enhances ?-Amyloid Clearance as a Potential Neuroprotective Mechanism against Alzheimer’s Disease: In Vitro and in Vivo Studies. ACS Chemical Neuroscience. An Error Occurred Setting Your User Cookie

Oleocanthal, a phenolic component of extra-virgin olive oil, has been recently linked to reduced risk of Alzheimer’s disease (AD), a neurodegenerative disease that is characterized by accumulation of ?-amyloid (A?) and tau proteins in the brain. However, the mechanism by which oleocanthal exerts its neuroprotective effect is still incompletely understood.

Here, we provide in vitro and in vivo evidence for the potential of oleocanthal to enhance A? clearance from the brain via up-regulation of P-glycoprotein (P-gp) and LDL lipoprotein receptor related protein-1 (LRP1), major A? transport proteins, at the blood-brain barrier (BBB). Results from in vitro and in vivo studies demonstrated similar and consistent pattern of oleocanthal in controlling A? levels.

In cultured mice brain endothelial cells, oleocanthal treatment increased P-gp and LRP1 expression and activity. Brain efflux index (BEI%) studies of 125I-A?40 showed that administration of oleocanthal extracted from extra-virgin olive oil to C57BL/6 wild-type mice enhanced 125I-A?40 clearance from the brain and increased the BEI% from 62.0 ± 3.0% for control mice to 79.9 ± 1.6% for oleocanthal treated mice. Increased P-gp and LRP1 expression in the brain microvessels and inhibition studies confirmed the role of up-regulation of these proteins in enhancing 125I-A?40 clearance after oleocanthal treatment. Furthermore, our results demonstrated significant increase in 125I-A?40 degradation as a result of the up-regulation of A? degrading enzymes following oleocanthal treatment.

In conclusion, these findings provide experimental support that potential reduced risk of AD associated with extra-virgin olive oil could be mediated by enhancement of A? clearance from the brain.

 

[cvictorg]

http://www.alnmag.com/news/hunger-protects-mice-against-alzheimers
The feeling of hunger itself may protect against Alzheimer’s disease, according to study published in the journal PLOS ONE. Interestingly, the results of this study in mice suggest that mild hunger pangs, and related hormonal pathways, may be as important to the much-discussed value of “caloric restriction” as actually eating less.

Study authors argue that hormonal signals are the middlemen between an empty gut and the perception of hunger in the brain, and that manipulating them may effectively counter age-related cognitive decline in the same way as caloric restriction.

“This is the first paper, as far as we are aware, to show that the sensation of hunger can reduce Alzheimer’s disease pathology in a mouse model of the disease,” says Inga Kadish, assistant professor in the Department of Cell, Developmental and Integrative Biology (CDIB) within the School of Medicine at the Univ. of Alabama at Birmingham. “If the mechanisms are confirmed, hormonal hunger signaling may represent a new way to combat Alzheimer’s disease, either by itself or combined with caloric restriction.”

The team theorizes that feeling hungry creates mild stress. That, in turn, fires up metabolic signaling pathways that counter plaque deposits known to destroy nerve cells in Alzheimer’s patients. The idea is an example of hormesis theory, where damaging stressors like starvation are thought to be good for you when experienced to a lesser degree.

To study the sensation of hunger, the research team analyzed the effects of the hormone ghrelin, which is known to make us feel hungry. They used a synthetic form of ghrelin in pill form, which let them control dosage such that the ghrelin-treated mice felt steadily, mildly hungry.

If it could be developed, a treatment that affected biochemical pathways downstream of hunger signals might help delay cognitive decline without consigning people to a life of feeling hungry. Straight caloric restriction would not be tolerable for many persons over the long-run, but manipulating post-hunger signaling might.

This line of thinking becomes important because any protective benefit brought about by drugs or diets that mildly adjust post-hunger signals might be most useful if started in those at risk as early in life as possible. Attempts to treat the disease years later – when nerve networks are damaged enough for neurological symptoms to appear – may be too late. In the current study, it was long-term treatment with a ghrelin agonist that improved cognitive performance in mice tested when they had reached an advanced age.

PLOS ONE: Hunger in the Absence of Caloric Restriction Improves Cognition and Attenuates Alzheimer's Disease Pathology in a Mouse Model
It has been shown that caloric restriction (CR) delays aging and possibly delays the development of Alzheimer's disease (AD). We conjecture that the mechanism may involve interoceptive cues, rather than reduced energy intake per se. We determined that hunger alone, induced by a ghrelin agonist, reduces AD pathology and improves cognition in the APP-SwDI mouse model of AD. Long-term treatment with a ghrelin agonist was sufficient to improve the performance in the water maze. The treatment also reduced levels of amyloid beta (A?) and inflammation (microglial activation) at 6 months of age compared to the control group, similar to the effect of CR. Thus, a hunger-inducing drug attenuates AD pathology, in the absence of CR, and the neuroendocrine aspects of hunger also prevent age-related cognitive decline.

 

[cvictorg]

Fasting can help protect against brain diseases, scientists say | Science | The Observer
Researchers at the National Institute on Ageing in Baltimore said they had found evidence which shows that periods of stopping virtually all food intake for one or two days a week could protect the brain against some of the worst effects of Alzheimer's, Parkinson's and other ailments.

"Reducing your calorie intake could help your brain, but doing so by cutting your intake of food is not likely to be the best method of triggering this protection. It is likely to be better to go on intermittent bouts of fasting, in which you eat hardly anything at all, and then have periods when you eat as much as you want," said Professor Mark Mattson, head of the institute's laboratory of neurosciences.

"In other words, timing appears to be a crucial element to this process," Mattson told the annual meeting of the American Association for the Advancement of Science in Vancouver.

Cutting daily food intake to around 500 calories – which amounts to little more than a few vegetables and some tea – for two days out of seven had clear beneficial effects in their studies, claimed Mattson, who is also professor of neuroscience at the Johns Hopkins University School of Medicine in Baltimore.

 

[Michael Scally MD]

Labs reject dramatic findings on cancer drug in Alzheimer's mice
Labs reject dramatic findings on cancer drug in Alzheimer's mice | Reuters

(Reuters) - U.S. scientists say a dramatic result last year suggesting that a cancer drug already approved by U.S. regulators could quickly clear out Alzheimer's plaques in mice was too good to be true.

The study, published last year in the journal Science, showed the skin cancer drug bexarotene cut the amount of an Alzheimer's-linked protein called beta amyloid by half in three days. It also reversed Alzheimer's symptoms, restoring a sense of smell in treated mice and allowing them to resume nest building activities.

The news sent patients clamoring for the drug, and some doctors began prescribing it, even though it had not been tested in people with Alzheimer's. But researchers at several U.S. centers reported in the same journal on Thursday that they were unable to reproduce the most dramatic aspects of the findings in their own labs.

 

[Michael Scally MD]

Drug Reverses Alzheimer's Disease Deficits in Mice
Drug reverses Alzheimer's disease deficits in mice

The research, funded by the National Institutes of Health's National Institute on Aging and Alzheimer's Association, reviewed previously published findings on the drug bexarotene, approved by the U.S. Food and Drug Administration for use in cutaneous T cell lymphoma. The Pitt Public Health researchers were able to verify that the drug does significantly improve cognitive deficits in mice expressing gene mutations linked to human Alzheimer's disease, but could not confirm the effect on amyloid plaques.

 

[Dr JIM]

Great post for CME credit IMO!

 

[Dr JIM]

Ya know it's is unfortunate, reports of this reminds us of the bitter truth, mice are NOT humans experimentally, which is why a "fast track" protocol is designed for devastating diseases such as ALZ with limited therapeutic options..

 

[Michael Scally MD]

A primary reason this has interest is Bexarotene is FDA Approved. TARGRETIN (BEXAROTENE) CAPSULE, LIQUID FILLED [EISAI INC.]

For more on the controversy, continue reading Response to Comments on “ApoE-Directed Therapeutics Rapidly Clear ?-Amyloid and Reverse Deficits in AD Mouse Models”

The basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden is unexplained. However, we concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.

Bexarotene Amyloid Treatment for Alzheimer's Disease (BEAT-AD)
Bexarotene Amyloid Treatment for Alzheimer's Disease - Full Text View - ClinicalTrials.gov

 

[zkt]

Targretin is a tier 5 drug, this means it is very expensive. An Internet search indicated that 30, 75mg capsules cost $1,156.64.

 

[zkt]

Since bexarotene is a highly selective retinoid X receptor (RXR) agonist I would assume its effectiveness is due to the RXR activity. Another RXR agonist is tretinoin which is almost dirt cheap. Further research is necessary to determine if RXR subgroup activities correspond in the two drugs and doseage. But it could be just possible that tretinoin would be also effective.

 

[cvictorg]

Higher blood sugar, even short of diabetes, may raise the risk of dementia, study suggests - The Washington Post

Higher blood-sugar levels, even those well short of diabetes, seem to raise the risk of developing dementia, a major new study finds. Researchers say it suggests a novel way to try to prevent Alzheimer’s disease — by keeping glucose at a healthy level.

The study involved 2,067 people 65 and older in the Group Health Cooperative, a Seattle-area health care system. At the start, 232 participants had diabetes; the rest did not. They each had at least five blood-sugar tests within a few years of starting the study and more after it was underway. Researchers averaged these levels over time to even out spikes and dips from testing at various times of day or before or after a meal.

Participants were given standard tests for thinking skills every two years and asked about smoking, exercise and other things that affect dementia risk.

After nearly seven years of follow-up, 524, or one quarter of them, had developed dementia — mostly Alzheimer’s disease. Among participants who started out without diabetes, those with higher glucose levels over the previous five years had an 18 percent greater risk of developing dementia than those with lower glucose levels.

Among participants with diabetes at the outset, those with higher blood sugar were 40 percent more likely to develop dementia than diabetics at the lower end of the glucose spectrum.

The effect of blood sugar on dementia risk was seen even when researchers took into account whether participants had the apoE4 gene, which raises the risk for Alzheimer’s.


MMS: Error

Methods

We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension.

Results

During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P=0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P=0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76).

Conclusions

Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. (Funded by the National Institutes of Health.)

 

[zkt]

" Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. (Funded by the National Institutes of Health.) "

IMHO, the study is tapping into the well established genetic defect that regulates glucose metabolism within specific regions of the brain. But they confuse the cause with the effect. Insulin resistance within brain tissue has a great effect on total... <insert paypal > LOL

 

[cvictorg]

http://newoldage.blogs.nytimes.com/2013/08/09/high-blood-sugar-linked-to-dementia/?hpw

http://www.geftakysassembly.com/Articles/Perspectives/Stress.htm

THE SELFISH BRAIN THEORY

The Selfish Brain: Stress and Eating Behavior

 

[edfriedman]

Researchers have shown that they can prevent the symptoms of Alzheimer's in transgenic male mice carrying an Alzheimer's-like gene by adding another mutation that knocks out aromatase activity. Not only did these mice not develop Alzheimer's, but their memories were better at their oldest ages than the memories of normal mice at any age!

The results of the mutation were significantly increased testosterone levels and no detectable estrogen. There is no way to introduce such a mutation in men, but you can add testosterone and administer an anti-aromatase drug to come close to the same conditions. This research was published in 2010 and is freely viewable at:
Genetic Targeting Aromatase in Male Amyloid Precursor Protein Transgenic Mice Down-Regulates ?-Secretase (BACE1) and Prevents Alzheimer-Like Pathology and Cognitive Impairment
I'm extremely disappointed that there has been no followup research in men since this mouse study was published. However, any doctor can treat a man with these off-label. Considering that Alzheimer's results in a horrible death every time it is not treated, I would hope that at least some doctor would try this protocol to save their patient's life and mind. Does anybody know of any men who were treated by this protocol and if so, what were the results?

Ed Friedman PhD

 

[Michael Scally MD]

The causes of the sporadic form of Alzheimer’s disease (AD) are unknown. In this study, researchers show that copper (Cu) critically regulates low-density lipoprotein receptor-related protein 1–mediated A? clearance across the blood–brain barrier (BBB) in normal mice. Faulty A? clearance across the BBB due to increased Cu levels in the aging brain vessels may lead to accumulation of neurotoxic A? in brains. In a mouse model of AD low levels of Cu also influences A? production and neuroinflammation. The study suggests that Cu may also increase the severity of AD.


Singh I, Sagare AP, Coma M, et al. Low levels of copper disrupt brain amyloid-? homeostasis by altering its production and clearance. Proceedings of the National Academy of Sciences. Low levels of copper disrupt brain amyloid-? homeostasis by altering its production and clearance

Whereas amyloid-? (A?) accumulates in the brain of normal animals dosed with low levels of copper (Cu), the mechanism is not completely known. Cu could contribute to A? accumulation by altering its clearance and/or its production. Because Cu homeostasis is altered in transgenic mice overexpressing A? precursor protein (APP), the objective of this study was to elucidate the mechanism of Cu-induced A? accumulation in brains of normal mice and then to explore Cu’s effects in a mouse model of Alzheimer’s disease. In aging mice, accumulation of Cu in brain capillaries was associated with its reduction in low-density lipoprotein receptor-related protein 1 (LRP1), an A? transporter, and higher brain A? levels. These effects were reproduced by chronic dosing with low levels of Cu via drinking water without changes in A? synthesis or degradation. In human brain endothelial cells, Cu, at its normal labile levels, caused LRP1-specific down-regulation by inducing its nitrotyrosination and subsequent proteosomal-dependent degradation due in part to Cu/cellular prion protein/LRP1 interaction. In APPsw/0 mice, Cu not only down-regulated LRP1 in brain capillaries but also increased A? production and neuroinflammation because Cu accumulated in brain capillaries and, unlike in control mice, in the parenchyma. Thus, we have demonstrated that Cu’s effect on brain A? homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma. These findings should provide unique insights into preventative and/or therapeutic approaches to control neurotoxic A? levels in the aging brain.

 

[Michael Scally MD]

 

[Michael Scally MD]

Artist with Alzheimer's Disease
http://www.nytimes.com/2006/10/24/health/24alzh.html

 

[cvictorg]

http://www.nytimes.com/2014/03/20/h...rain-from-alzheimers-study-finds.html?hp&_r=0

It is one of the big scientific mysteries of Alzheimer’s disease: Why do some people whose brains accumulate the plaques and tangles so strongly associated with Alzheimer’s not develop the disease?

Now, a series of studies by Harvard scientists suggests a possible answer, one that could lead to new treatments if confirmed by other research.

The memory and thinking problems of Alzheimer’s disease and other dementias, which affect an estimated seven million Americans, may be related to a failure in the brain’s stress response system, the new research suggests. If this system is working well, it can protect the brain from abnormal Alzheimer’s proteins; if it gets derailed, critical areas of the brain start degenerating.

 

[Michael Scally MD]

Hall JR, Wiechmann AR, Cunningham RL, Johnson LA, Edwards M, et al. Total testosterone and neuropsychiatric symptoms in elderly men with Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):24. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416299/

INTRODUCTION: There has been a significant increase in the use of testosterone in aging men, but little investigation into its impact on men with Alzheimer's disease (AD). The findings of the few studies that have been done are inconsistent. In the present study, we investigated the relationship between total testosterone (TT) and neuropsychiatric symptoms (NPS) in a well-characterized sample of elderly men with mild to moderate AD.

METHODS: The sample, which was drawn from the Texas Alzheimer's Research Care Consortium Longitudinal Research Cohort, included 87 men who met the criteria for mild to moderate AD. The occurrence of NPS was gathered from caregivers and/or family members with the Neuropsychiatric Inventory. TT was analyzed, and the sample was divided into a low-testosterone group (TT </=2.5 ng/ml; n = 44) and a borderline/normal group (TT >/=2.6 ng/ml; n = 43).

RESULTS: TT was correlated with symptoms of hallucinations, delusions, agitation, irritability and motor activity. The borderline/normal group was significantly more likely to have hallucinations (odds ratio (OR) = 5.56), delusions (OR = 3.87), motor activity (OR = 3.13) and irritability (OR = 2.77) than the low-testosterone group. Health status and apolipoprotein E epsilon4 status were not significant factors.

CONCLUSIONS: The findings of the present study have implications for the use of testosterone replacement therapy in men with AD or the prodromal stage of the disease.

 

[jonkobeck]

If I ever had to go down that road I would check-out. I'm not having none of that