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Potential of Mushroom Supplementation to Inhibit Progression of Alzheimer´s Disease

by Prof Vittorio Calabrese and Maria Laura Ontario(more info)

listed in neurological, originally published in issue 232 - August 2016

Introduction

The World Health Organization reports that 47.5 million people are affected by dementia worldwide. With ageing populations and 7.7 million new cases each year, the burden of illness due to dementia approaches crisis proportions. Due to increased life expectancy, the prevalence of cognitive decline related to neurodegenerative diseases and to non-neurological conditions is increasing in western countries. Within this context, dementia is a syndrome associated with progressive declines in cognitive capacities and impairments that interfere with daily functioning. These conditions are the primary cause of dependency, disability and institutionalization among older populations.[1]

In 2015, one estimate is that 46.8 million persons have dementia worldwide; this number is expected to grow to 131.5 million by 2050.[2] Five (5) percent of people from age sixty-five (65) to seventy-four (74) have Alzheimer´s, but more than fifty (50) percent of those over eighty-five (85) have it, even if they have no obvious risk factors.[3] 

The estimated cost of dementia is estimated to be $816 billion and expected to grow to 1 trillion by 2018.[4] Furthermore, a UK study estimates that the health and social costs for dementia almost match the combined cost of cancer, heart disease and stroke.[5] In sum, the economic cost of Alzheimer´s (AD) is staggering and threatens the healthcare budgets of many countries.

In 2014, one of the objectives of the Global Action Against Dementia was to identify a cure or disease-modifying therapy for dementia by 2015. The objective of this paper is to propose a disease-modifying therapy for dementia based on the use of mushroom nutrition.[6]

What causes Dementia and Impact on Memory Processes?

Evidence from the last decades has revealed that genetic, vascular and lifestyle-related risk factors often co-occur across the lifespan and interact to determine the risk of developing dementia and AD later in life.[7] With respect to the latter, while the precise underlying aetiology of AD is unknown, extensive knowledge is available regarding its clinical and pathological features. The neuro-pathological hallmarks of AD involve the formation of extracellular beta amyloid (Ab) plaques and intra-neuronal neurofibrillary tangles, which are both associated with synaptic and neuronal loss.

Risk Factors and Protective Factors

Figure 1: Risk Factors and Protective Factors

Dementia and AD are multifactorial disorders (Figure 1). Hypotheses regarding the cause of dementia have also changed over time. As recently as the 1960s, a vascular aetiology was the prevailing view, while now it is increasingly reported that mixed pathology dementias account for half or more of all dementia cases, with beta-amyloid and vascular disease constituting the most frequent combination of pathologies. Atherosclerosis, arteriosclerosis, micro-infarcts, silent stroke, and diffuse white matter disease are all associated with increased risk of dementia. Recent evidence suggests an association between mid-life hypertension, a major risk factor for stroke and diffuse white matter disease, and mid-life obesity with future risk of dementia.

Dementia can be caused by:

  1. Cerebrovascular diseases (Silent stroke, micro-infarcts, arteriosclerosis)
  2. TBI
  3. Hypertension
  4. AD

In all these conditions an increased burden of beta  amyloid occurs and neuro-inflammations ensues.

The most common cause of dementia is Alzheimer´s disease (AD).[7] Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions lead to amyloid deposition, neurofibrillary tangle formation and premature neuronal death, the major neuro-pathological hallmarks of AD.[8]

Steps in Creation of Short Term and Long Term Memory

Figure 2. Steps in Creation of Short Term and Long Term Memory

To understand Alzheimer´s disease pathogenesis, Figure 2 provides a schematic illustration on the anatomical basis. Essentially, sensory information (e.g. vision, touch, taste) first pass through the brain stem to the thalamus (Step 1), which acts like a relay station, directing the signals to the various sensory lobes of the brain (Step 2), where they are evaluated. The processed information reaches the prefrontal cortex (Step 3), where it enters the consciousness and forms our short-term memory, which can range from several seconds to minutes.[9]

To store information for a longer duration, these are broken down into different categories in the hippocampus (Step 4), where the fragments are redirected to various cortical structures. For instance, emotional memories are stored in the amygdale, but words are recorded in the temporal lobe. Meanwhile, colours and other visual information are collected in the occipital lobe, and the sense of touch and movement reside in the parietal lobe.[10] The ultimate goal of research focusing on learning and memory processes is, then, to figure out how these scattered fragments are somehow reassembled when we recall an ‘experience’. This is called the “binding problem”. Elevated β-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the "transfer" of new learning across a wide variety of contexts. Thus, understanding this “binding problem” could potentially unravel novel targets for more efficient therapeutic approach to AD-derived dementia.[11-15]  

Alzheimer's disease (AD) is an age-related neurodegenerative disease of the central nervous system correlated with the progressive loss of cognition and memory. β-Amyloid plaques, neurofibrillary tangles and the deficiency in cholinergic neurotransmission constitute the major hallmarks of the AD.[16,17] Two major hypotheses have been implicated in the pathogenesis of AD. namely the cholinergic hypothesis which ascribed the clinical features of dementia to the deficit cholinergic neurotransmission and the amyloid cascade hypothesis which emphasized on the deposition of insoluble peptides formed due to the faulty cleavage of the amyloid precursor protein. Current pharmacotherapy includes mainly the acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor agonist which offer symptomatic therapy and does not address the underlying cause of the disease. The disease-modifying therapy has garnered a lot of research interest for the development of effective pharmacotherapy for AD. β and γ-Secretase constitute attractive targets that are focused in the disease-modifying approach. Potentiation of α-secretase also seems to be a promising approach towards the development of an effective anti-Alzheimer therapy. Additionally, the ameliorative agents that prevent aggregation of amyloid peptide and also the ones that modulate inflammation and oxidative damage associated with the disease are focused upon. On the other hand, development in the area of the vaccines is in progress to combat the characteristic hallmarks of the disease.[18]

The genetic, cellular, and molecular changes associated with Alzheimer disease provide evidence of immune and inflammatory processes involvement in its pathogenesis. These are supported by epidemiological studies, which show some benefit of long-term use of NSAID. The hypothesis that AD is in fact an immunologically mediated and even inflammatory pathological process may be in fact scientifically intriguing. There are several obstacles that suggest the need for more complex view, in the process of targeting inflammation and immunity in AD. In 2000, researchers led by Dr Frank M LaFerla at the Department of Neurobiology and Behavior at the University of California Irvine, Irvine, USA, demonstrated that a synthetic protein that resembles the Herpes Simplex Virus (HSV-1) mimics the structure and function of a protein called β-amyloid, the toxic agent that accumulates in the brains of Alzheimer patients.[18,19] Moreover, genetic sequencing revealed that two-thirds of the viral protein is identical to the β-amyloid protein, and also, the viral protein generates abnormally twisted fibers similar to those found in AD brain brains (neurofibrillary tangles, formed of hyper-phosphorylated ‘tau’ protein)  representing one of the hallmark of the disease.[19,20]

Several data indicate that neuronal infection with herpes simplex virus type 1 (HSV-1) causes biochemical alterations reminiscent of Alzheimer's disease (AD) phenotype. They include accumulation of amyloid-β (Aβ), which originates from the cleavage of amyloid precursor protein (APP), and hyper-phosphorylation of tau protein, which leads to neurofibrillary tangle deposition. HSV-1 infection triggers APP processing and drives the production of several fragments including APP intracellular domain (AICD) that exerts trans-activating pro-inflammatory properties. Although a recent study indicated unequivocally lack of evidence for a role of HHV-6 in the pathogenesis of Alzheimer's disease,[21] still there are evidence indicating that, for instance, HSV-1 infection might induce early upstream events in the cell that may eventually lead to Aβ deposition and tau hyper-phosphorylation and further suggest HSV-1 as a possible risk factor for AD.[22-27]

Increasing evidence indicates that aspirin-triggered Lipoxin A4 (LXA4) (15 μg/kg) s c, twice a day, reduced both NF-kB activation and levels of pro-inflammatory cytokines and chemokines, as well as increased levels of anti-inflammatory IL-10 and transforming growth factor B (beta). Basically, LXA4 seems to reduce brain inflammation.[28] Such changes in the cerebral milieu resulted in recruitments of microglia in an alternative phenotype as characterized by the up-regulation of Ym1 and arginase-1 and the down-regulation of inducible nitric oxide synthase expression.[10] In effect, the researchers contend that activating LXA4 signaling may represent a novel therapeutic approach for AD.[28] Given the potential gastrointestinal discomfort associated with aspirin intake, is there another manner to increase LXA4 in the brain as well as provide both anti-viral protection and anti-oxidant protection?

Coriolus Mushroom

Coriolus versicolor

Why Mushroom Nutrition?

In the past ten years, the clinical development of mushroom nutrition has determined that Coriolus versicolor (biomass) has viral protective properties, while Hericium erinaceus (biomass) is extremely high in SOD content. Consistent with this notion Coriolus versicolor biomass has a clinically verified use in the reduction of viral load of EBV, CMV and HHV-6. These viruses are related to the onset of Chronic Fatigue Syndrome condition.[29,30] In addition, Coriolus versicolor has been used to increase the regression rate of LSIL lesions in HPV patients and to significantly reduce the viral load in HPV patients.[31]

Hericium erinaceus biomass has an extremely high super-oxide dismutase (SOD) content , which in the presence of in vitro proteolytic enzymes (per 500 mg tablet) has a SOD content of 19.430 10³ U.[32] This high SOD content is important given that with Herpes Simplex virus infection, apoE4 intensifies virus latency and is associated with the increased oxidative damage to the central nervous system. In addition there is some evidence that herpes simplex virus infection in combination with the apoE4 genotype may be associated with increased risk of Alzheimer´s disease (AD).[33]

Assessing the Capacity of Coriolus versicolor to Increase LXA4

LXA4, a metabolic product of arachidonic acid, is considered an endogenous ‘stop signal’ for inflammation and demonstrates strong anti-inflammatory properties in many inflammatory disorders, such as nephritis, periodontitis or arthritis.[34] Chronic brain inflammation sustains the progression of Alzheimer´s disease, so the objective is to find molecules that can reduce brain inflammation; thereby providing a disease-modifying therapy for dementia.

Researchers in the University of Catania and the University of Messina conducted research to determine if Coriolus versicolor biomass stimulates Lipoxin A4 (LXA4) activation in peripheral blood and in the CNS of rats treated with an equivalent human dose of 3g per day given, orally. One group of rats were supplemented with Coriolus versicolor biomass and another group (Control) that was not supplemented over 30 days (N=10).[35]

At the end of experimental period animals were sacrificed and the activity of LXA4 was determined in serum, lymphocytes and in different brain regions (cortex, striatum, substantia nigra, hippocampus and cerebellum) and compared with LXA4 of untreated animals, as control.[35]

The researchers focused on the impact of Coriolus supplementation on redox-dependent genes, called vitagenes, including heat shock proteins (Hsps), sirtuins, thioredoxin and lipoxin A4 (LXA4). The differences in the up-regulation of the following vitagenes were measured:

a. Lipoxin A4 (LXA4)

b. Heme Oxygenase-1 (HO-1);

c. Heat Shock Protein 70 (Hsp 70).

d. Thioredoxin

LXA4

Bar Chart LXA4

Fig 3 Bar Chart LXA4

Fig. 3. Regional distribution of Lipoxin A4 protein levels in different brain regions and in total brain of control or Coriolus-fed rats. Values are expressed as mean SEM of three independent analyses on 10 animals per group. CX: cortex; Hp: hippocampus; Cb: cerebellum; TB: total brain. C: Coriolus, given orally at the dose of 200 mg/kg for 30 days.

As outlined in Figure 3, higher levels of LXA4 protein expression was observed in cortex and  cerebellum, followed with a statically significant difference by striatum, hippocampus and septum, whereas the lowest levels were found in the substantia nigra.

Administration of Coriolus versicolor for 30 days at the oral daily dose of 200 mg/kg induced an increase in the protein levels of LXA4 in all brain regions examined. This effect was significant (P<0.05) in the cortex, hippocampus and in the total brain compared to control group, but not in the cerebellum.

LXA4 Levels

Fig 4 LXA4 Levels

Fig. 4. (A) LXA4 levels in plasma from rats fed Coriolus biomass preparation as compared to the control group. Data are expressed as mean SEM of 10 animals per group. *P < 0.05 vs controls; (B) LXA4 levels in liver, kidney and in lymphocytes from rats fed Coriolus biomass preparation as compared to control group. Data are expressed as mean SEM of 10 animals per group. *P < 0.05 vs controls.

As outlined in Figure 4, animals receiving chronic administration of Coriolus compared to untreated controls, brain changes in LXA4 protein were associated with a significant (P<0.05) increase in plasma (Figure 4 A), lymphocytes and peripheral organs, such as liver and kidney (4B).

Heme Oxygenase-1

Heme oxygenase-1

Fig 5 Heme oxygenase-1

Fig. 5. Heme oxygenase-1 protein levels in the brain of rats fed Coriolus biomass preparation as compared to the control group. Total brain homogenates from control and mushroom-supplemented rats were assayed for HO-1 expression by Western blot. (A) Densitometric evaluation: the bar graph shows the values are expressed as mean standard error of mean of three independent analyses. P < 0.05 vs control. (B) A representative immunoblot is shown. b-Actin has been used as loading control. D.U., densitometric units.

As demonstrated in Figure 5, Coriolus supplementation resulted in up-regulation of brain cellular stress response protein heme oxygenase-1 (HO-1).

Hsp 70

Hsp 70 Inducible shock protein

Fig 6 Hsp 70 Inducible shock protein

Fig. 6. Inducible Heat shock protein 70 protein levels in the brain of rats fed Coriolus biomass preparation as compared to control group. Total brain homogenates from control and mushroom supplemented rats were assayed for Hsp70 expression by Western blot. (A) Densitometric evaluation: the bar graph shows the values are expressed as mean standard error of mean of three independent analyses. P < 0.05 vs control. (B) A representative immunoblot is shown. b-Actin has been used as loading control. D.U., densitometric units.

Levels of Hsp 70 were significantly increased in the cortex, substantia nigra and hippocampus (Figure 6).

Impact of Coriolus supplementation on up-regulation of OH-1 and Hsp70 on Cortex, Substantia Nigra and Hippocampus

Representative Blots different brain regions for HO-1 and Hsp 70

Fig 7 Representative Blots different brain regions for HO-1 and Hsp 70

Fig. 7. Representative Western blots, obtained probing the different brain regions for HO-1 (A) and, respectively Hsp70 (B) proteins. CX: cortex; Hp: hippocampus; SN: substantia nigra.

Figure 7 is a representative Western blot, obtained probing the different brain regions for HO-1 (Figure 7A) and respectively, Hsp 70 (Figure 7B) proteins, which show a significant increase of proteins  levels induced by Coriolus supplementation in the cortex , substantia nigra and hippocampus.[35]

Heme Oxygenase-1 in Blood Plasma

Heme oxygenase-1 protein levels in plasma

Fig 8 Heme oxygenase-1 protein levels in plasma

Fig. 8. Heme oxygenase-1 protein levels in plasma from rats fed Coriolus biomass preparation as compared to the control group. Samples from control and mushroom supplemented rats were assayed for HO-1 expression by Western blot. (A) Densitometric evaluation: the bar graph shows the values are expressed as mean standard error of mean of three independent analyses. P < 0.05 vs control. (B) A representative immunoblot is shown. b-Actin served as the loading control. D.U., densitometric units.

As outlined in Figure 8, there was a significant induction of heme oxygenase-1 in the plasma of Coriolus fed rats when compared to the Control group of rats.

Thioredoxin

Thioredoxin protein levels

Fig 9 Thioredoxin protein levels

Fig. 9. Thioredoxin protein levels in the brain of rats fed Coriolus biomass preparation as compared to the control group. Total brain homogenates from control and mushroom-supplemented rats were assayed for thioredoxin (Trx) by Western blot. (A) Densitometric evaluation: the bar graph shows the values are expressed as mean standard error of mean of three independent analyses. P < 0.05 vs control. (B) A representative immunoblot is shown. b-Actin has been used as loading control. D.U., densitometric units.

As outlined in Figure 9, there was a significant increased expression of redox-sensitive thioredoxin in total brain homogenate of Coriolus fed rats when compared to the Control group of rats.

Conclusion

Coriolus versicolor biomass supplementation has been shown to significantly up-regulate LXA4 in the brain in rats when compared to a control group. In addition, there was a significant increase in heme oxygenase-1, Hsp 70 and  thioredoxin in the total brain of Coriolus-fed rats when compared to a control group.[35]

These results could have implications for the development of a mushroom nutrition based, disease-modifying therapy, for the treatment of Alzheimer´s disease. The next step is to construct a clinical trial that provides a ‘proof of concept’ in patients. This finding has been further refined and consolidated in a subsequent study indicating the powerful therapeutic potential of a supplementation with  mushroom nutrition in the control of neuroinflammatory alterations sustaining the pathogenesis of Alzheimer’s disease with potential impact on the course and the progression of the disease.[36]

Note: The Coriolus versicolor biomass was supplied by Mycology Research Laboratories Ltd.-United Kingdom. (www.mycologyresearch.com)

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About Prof Vittorio Calabrese and Maria Laura Ontario

Prof Vittorio Calabrese MD is a full Professor of Clinical Biochemistry School Of Medicine, University of Catania, Department of Biomedical and Biotechnological Sciences. He is a member of the Editorial Board of several high peer reviewed journals including: Journal of Neuroscience Research;  Neurochem Research;  Antioxidant Redox Signaling; Journal Neurochemistry;  Free Radical Biology Medicine; Current Neurovascular Disorders. He has been reviewer of national projects (Italian MIUR), and foreign projects and a member of the ASN Commission (05/E1) of the Italian MIUR for 2013 and 2014. His research focuses on the role of free radicals and antioxidants in human disease, particularly Alzheimer's disease and other brain disorders; identifying the most important antioxidants in the human diet and in developing novel antioxidants has a critical bearing on treating human diseases and understanding how diet might cause or prevent them. Areas of his research interests includes role of Oxidative Stress and Mitochondrial dysfunction in Ageing, Neurodegenerative disorders and Longevity; Proteomics and redox proteomics, Heat shock signal pathway Hormesis and Vitagenes in Neurodegeneration. The results of his researches have been reported in over 160 scientific papers published in international journals and widely cited (around 8500 total citations, around 5000 citations of the 10 most cited articles), for an HI value of 57 (ISI). He has deposited one patent (Nr. WO 2004/07883 A1 of  10.9.2004) for the use of curcumin and its derivatives in the treatment neurodegenerative disorders. Prof Calabrese may be contacted via email at calabres@unict.it

Maria Laura Ontario PhD molecular biology at the University of Catania, Catania, Italy, thesis on  Molecular Genetics, is current student in Bio-Molecular Chemistry at the University of Catania. She has spent a training period at Institute of Human Virology of Maryland, and attended many workshops. She is chief scientific officer and Health Department Director at Ontario S.r.l, (Health and Scientific Division, Research & Development Division); and Director for first aid management Trapani Airport, Airgest Spa, Director for first aid management Cagliari Airport Sogaer. She is also Manager of Medical Nursing and Management of Occupational Medicine and Biologist at Central laboratory Medicine, Polyclinic, University of Catania. Her research focuses on the role of free radicals and antioxidants in human disease, particularly neurodegenerative diseases. The results of her researches have been reported in 8 papers published in peer reviewed international journals. She has deposited one patent Nr. RM2011U000138 5/09/2011 for a medical device.

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  • nEW VISTAS HEALTHCARE

    Encourages health, strength, balance through homeopathy, nutrition, herbs, supplements, kinesiology.

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  • College of Ayurveda UK

    Diploma in Āyurvedic Healthcare, 3-year self-paced distant learning program in Āyurvedic medicine.

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  • The Listening Centre

    London UK Centre for Tomatis Listening Therapy voice, language, depression, autism, dyslexia, stroke

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  • Nutritional gut health

    Comprehensive self-study online practitioner course to identify causes patients digestive symptoms

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    Specialist online health store focused on hydration, body pH balance and quality nutrition.

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  • Rayonex Bioresonance

    Devices vibrational medicine full range of applications and accessories research and clinical usage

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  • June Sayer Homeopathy

    Training Academy Homeopathy Nutrition Reiki, Distant Learning. Diet, Health Screening, Detox, Stress

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  • Seaweed as Superfood

    Comprehensive nutrient balance found in no other natural food but seaweed: colon health, weight loss

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  • PROFESSOR Sheik IMAM

    Professor Sheik Imam is a famous professional leading African Healer who works with powerful spirits

    www.besthealer.co.uk

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