Brain aging is one of the inevitable signs of aging. Cognitive decline and dementia takes many forms, among the most common is Alzheimer's Disease (AD). AD is estimated to comprise 60-70% of all dementia cases worldwide. Similarly, the report from the
World Health Organization (WHO) states that "dementia is one of the major causes of disability and dependency among older people worldwide." (1) At this time, the only medicines available to treat AD only treat the symptoms and have no effect on the progression of the disease. In the near future, it is estimated that cases of AD will grow at an alarming rate, given the aging of the world's population.
Aging is the primary risk factor for Alzheimer's Disease. Neuronal cell death and synaptic degradation in Alzheimer's is attributed to gradual build-up of toxic mis-folded proteins (beta amyloid) and aggregation of tau protein fibrils and chronic brain inflammation. Each of these defective proteins kill neurons and synapses, rendering a degeneration of brain physical and mental function.
Yellows and golds in nature support brain health, and may reduce some of the factors associated with Alzheimer's Disease based upon animal research models. Research is strongly supportive of the role yellows can play in defusing brain inflammation, protecting against beta amyloid toxicity, tau fibril aggregation, microvascular circulation and provide protection of vital neurons and synapses.
RESEARCH - FACTORS INVOLVED IN BRAIN HEALTH
(1) Glycogen synthase kinase 3 (GSK3) - a kinase enzyme which has been implicated in many diseases including Alzheimer's Disease, type 2 diabetes and cancer. In Alzheimer's Disease GSK3 has a key role in the accumulation of the toxic proteins. Inhibitors of GSK3 reduce beta amyloid and tau protein toxic buildup and are now a target of researchers.(2)
(2) Beta Amyloid and Neurofibrillary (Tau) Tangles - Consensus of the scientific community is that beta amyloid, a toxic protein in the brain, is the initiator for further cascading events in the Alzheimer's progression. Beta amyloid accumulation then triggers a second protein toxin tau protein tangles (tau hyperphosphorylation).(3) Both proteins act as neurotoxins in the neurons and synapses. It appears that the over accumulation of Beta Amyloid stems from increased production and the inability to remove the excess.(4) This could involve a defect in the cellular ability to remove defective proteins (proteolysis including autophagy) (5) and / or an impairment of cerebral fluid removal system from the brain of the toxic proteins.
(3) Chronic Microglial Inflammation Over stimulation of the microglia in the brain is a primary cause of neuro inflammation. Microglia in brain become overly activated as a result of beta amyloid accumulation - theryby creating an inflammatory state in the brain, which further accelerates the destruction of brain neurons and synapses. (6)
Paradoxically, microglia may also play a protective role by clearing amyloid plaque via phagocytosis. Nrf2 activation in the microglia may support increase in phagocytosis activity, which has been demonstrated using sulforphane in test animals in brain hematoma clearance.(7) Sulforaphane also provides direct protection to brain from amyloid.(8) Furthermore, studies indicate that taurine is able to reduce inflammation in the brain by switching the type of microglia from M1 (proinflammatory) to M2 (which promotes phagocytosis).(9) Taurine also acts directly on protein aggregates ameliorating toxicity.(10)
(4) Defective insulin Signaling (Type 2 diabetes). There is a strong association between type 2 diabetes and cognitive decline.(11, 12) Insulin resistance in the brain, associated with type 2 diabetes, is correlated with Alzheimer's Disease.(12) Insulin resistance increases tau protein hyperphosphorylation (forming toxic tau protein tangles). EGCG (from Green Tea) has been shown to attenuate insulin resistance in the hippocampus area of the brain, thereby improving memory deficits related to Alzheimer's Disease. As part of the effect, EGCG inhibited glycogen synthase kinase-3β (GSK3), which plays a role in insulin resistance. Diet induced insulin resistance also has been shown to increase the manufacture of beta amyloid in the brain.(13)
(5) Vascular Circulation (in brain) There is a strong correlation between neurovascular disorder and intensity of brain dysfunction in the progression of Alzheimer's Disease.(14) Decline in blood flow to the brain affects the neurons and their ability to function and survive. Areas of the brain which deficient blood flow show white areas in brain MRIs, referred to as "white matter lesions" and are common in the brains of Alzheimer's patients and are caused by affected blood flow to a region of the brain.(15) Patients with white matter lesions are associated with more rapid decreased cognition (16) and also contribute to occurrence of depression experienced in Alzheimer's patients.(17)
(6) Iron and Brain Aging. While iron is a necessary mineral for good health, excessive accumulation in the brain is highly oxidative and inflammatory. Removal of excess iron from the brain, and iron homeostasis, will support healthy brain function and reduce potential for neurodegenerative diseases such as Alzheimers. Iron chelators, which remove excess cellular iron are effective in promoting brain health.(18)
KEY INGREDIENTS FOR SUPPORT OF BRAIN HEALTH
(1) World Health Organization (WHO). Dementia. March 2015.
(2) Maqbool M, et al. Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease. Eur J Med Chem. 2015 Oct 21
(3) Musiek ES, et al. Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci. 2015 Jun
(4) Gallina P, et al. Aβ Clearance, “hub” of Multiple Deficiencies Leading to Alzheimer Disease. Front Aging Neurosci. 2015;
(5) Salminen A, et al. Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome. Prog Neurobiol. 2013 Jul-Aug.
(6) Wang WY, et al. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 2015 Jun
(7) Zhao X, et al. Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance. J Neurochem 2015 Apr
(8) Zhang R, et al. Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid β deposits and peroxidation in mice with Alzheimer-like lesions. Am J Alzheimers Dis Other Demen. 2015 Mar.
(9) Ward RJ, et al. Ageing, neuroinflammation and neurodegeneration. Front Biosci (Schol Ed) 2015 Jun
(10) Chaturvedi SK, et al. Biophysical insight into the anti-amyloidogenic behavior of taurine. Int J Biol Macromol. 2015 Sep
(11) Li M, et al. Fasting and systemic insulin signaling regulate phosphorylation of brain proteins that modulate cell morphology and link to neurological disorders. J Biol Chem. 2015 Oct 23
(12) Sato N, et al. The roles of lipid and glucose metabolism in modulation of β-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease. Front Aging Neurosci 2015 Oct
(13) Ho L, et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 2004 May
(14) Pachalska M, et al. Vascular Factors and Cognitive Dysfunction in Alzheimer Disease. Med Sci Monit. 2015 Nov
(15) Alzheimer's Society. 2015.
(17) Lee JJ, et al. Impact of White Matter Lesions on Depression in the Patients with Alzheimer's Disease. Psychiatry Investig 2015 Oct
(18) Ward RJ, et al. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014 Oct
ALZHEIMERS INGREDIENTS RESEARCH:
(19) Tapia-Rojas C, et al. Andrographolide activates the canonical Wnt signalling pathway by a mechanism that implicates the non-ATP competitive inhibition of GSK-3β: autoregulation of GSK-3β in vivo. Biochem J. 2015 Mar 1
(20) Wang C, et al. Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice. Eur J Pharmacol. 2014 Oct
(21) Venigalla M, et al. Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease. Neurochem Int. 2015 Oct 31
(22) Venigalla M, et al. Curcumin and Apigenin - novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease. Neural Regen Res. 2015 Aug;
(23) Jia N, et al. (-)-Epigallocatechin-3-gallate alleviates spatial memory impairment in APP/PS1 mice by restoring IRS-1 signaling defects in the hippocampus. Mol Cell Biochem. 2013 Aug
(24) de Oliverira. The Dietary Components Carnosic Acid and Carnosol as Neuroprotective Agents: a Mechanistic View. Mol Neurobiol. 2015 Nov 9
(25) Rasoolijazi H, et al. The protective role of carnosic acid against beta-amyloid toxicity in rats. Scientific WorldJournal 2013 Oct 24
(26) Azad N, et al. Neuroprotective effects of carnosic Acid in an experimental model of Alzheimer's disease in rats. Cell J. 2011 Spring.
(27) Shi X, et al. Curcumin inhibits Aβ-induced microglial inflammatory responses in vitro: Involvement of ERK1/2 and p38 signaling pathways. Neurosci Lett. 2015 May
(28) Rezai-Zadeh K, et al. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J Neuroinflammation. 2008 Sep 25
(29) Park SY, et al. α-Iso-cubebene exerts neuroprotective effects in amyloid beta stimulated microglia activation. Neurosci Lett. 2013 Oct 25
(30) Bustanji Y, et al. Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluation. J Enzyme Inhib Med Chem. 2009 Jun.
(31) Mathew M, et al. In vitro evaluation of anti-Alzheimer effects of dry ginger (Zingiber officinale Roscoe) extract.
(32) Dong HJ, et al. Curcumin attenuates ischemia-like injury induced IL-1β elevation in brain microvascular endothelial cells via inhibiting MAPK pathways and nuclear factor-κB activation. Neuro Sci. 2014 Sep
(33) Mann GE. Nrf2-mediated redox signalling in vascular health and disease. Free Radic Biol Med. 2014 Oct.
(34) Baum L, et al. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis. 2004 Aug
(35) Oboh G, et al. Antioxidant and inhibitory effect of red ginger (Zingiber officinale var. Rubra) and white ginger (Zingiber officinale Roscoe) on Fe(2+) induced lipid peroxidation in rat brain in vitro. Exp Toxicol Pathol. 2012 Jan
(36) Hofer T, et al. Comparison of food antioxidants and iron chelators in two cellular free radical assays: strong protection by luteolin. J Agric Food Chem. 2014 Aug 20
(37) Mladěnka P, et al. In vitro analysis of iron chelating activity of flavonoids. J Inorg Biochem. 2011 May
(38) Mandel SA, et al. Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG). J Alzheimers Dis. 2008 Oct
(39) Lavich IC, et al. Sulforaphane rescues memory dysfunction and synaptic and mitochondrial alterations induced by brain iron accumulation. Neuroscience. 2015 Aug 20.