Alzheimers Abstracts 11

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Cannabinoids in late-onset Alzheimer's disease.
            (Ahmed et al., 2015)  Download
Given the lack of effective treatments for late-onset Alzheimer's disease (LOAD) and the substantial burden on patients, families, health care systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety, and pharmacokinetics of cannabinoid-based drugs in older people with dementia.

Zinc Deficiency and Zinc Therapy Efficacy with Reduction of Serum Free Copper in Alzheimer's Disease
            (Brewer and Kaur, 2013)  Download
We are in the midst of an epidemic of Alzheimer's disease (AD) in developed countries. We have postulated that ingestion of inorganic copper from drinking water and taking supplement pills and a high fat diet are major causative factors. Ingestion of inorganic copper can directly raise the blood free copper level. Blood free copper has been shown by the Squitti group to be elevated in AD, to correlate with cognition, and to predict cognition loss. Secondly, we have shown that AD patients are zinc deficient compared to age matched controls. Zinc is important in neuronal protection. We carried out a 6-month small double blind trial of a new zinc formulation on AD patients. We found that in patients 70 years and older, zinc therapy protected against cognition decline compared to placebo controls. We also found that zinc therapy significantly lowered blood free copper levels. So zinc efficacy could be due to restoring neuronal zinc levels, to lowering blood free copper levels, or to both.


 

Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial.
            (Chew et al., 2015)  Download
IMPORTANCE:  Observational data have suggested that high dietary intake of saturated fat and low intake of vegetables may be associated with increased risk of Alzheimer disease. OBJECTIVE:  To test the effects of oral supplementation with nutrients on cognitive function. DESIGN, SETTING, AND PARTICIPANTS:  In a double-masked randomized clinical trial (the Age-Related Eye Disease Study 2 [AREDS2]), retinal specialists in 82 US academic and community medical centers enrolled and observed participants who were at risk for developing late age-related macular degeneration (AMD) from October 2006 to December 2012. In addition to annual eye examinations, several validated cognitive function tests were administered via telephone by trained personnel at baseline and every 2 years during the 5-year study. INTERVENTIONS:  Long-chain polyunsaturated fatty acids (LCPUFAs) (1 g) and/or lutein (10 mg)/zeaxanthin (2 mg) vs placebo were tested in a factorial design. All participants were also given varying combinations of vitamins C, E, beta carotene, and zinc. MAIN OUTCOMES AND MEASURES:  The main outcome was the yearly change in composite scores determined from a battery of cognitive function tests from baseline. The analyses, which were adjusted for baseline age, sex, race, history of hypertension, education, cognitive score, and depression score, evaluated the differences in the composite score between the treated vs untreated groups. The composite score provided an overall score for the battery, ranging from -22 to 17, with higher scores representing better function. RESULTS:  A total of 89% (3741/4203) of AREDS2 participants consented to the ancillary cognitive function study and 93.6% (3501/3741) underwent cognitive function testing. The mean (SD) age of the participants was 72.7 (7.7) years and 57.5% were women. There were no statistically significant differences in change of scores for participants randomized to receive supplements vs those who were not. The yearly change in the composite cognitive function score was -0.19 (99% CI, -0.25 to -0.13) for participants randomized to receive LCPUFAs vs -0.18 (99% CI, -0.24 to -0.12) for those randomized to no LCPUFAs (difference in yearly change, -0.03 [99% CI, -0.20 to 0.13]; P = .63). Similarly, the yearly change in the composite cognitive function score was -0.18 (99% CI, -0.24 to -0.11) for participants randomized to receive lutein/zeaxanthin vs -0.19 (99% CI, -0.25 to -0.13) for those randomized to not receive lutein/zeaxanthin (difference in yearly change, 0.03 [99% CI, -0.14 to 0.19]; P = .66). Analyses were also conducted to assess for potential interactions between LCPUFAs and lutein/zeaxanthin and none were found to be significant. CONCLUSIONS AND RELEVANCE:  Among older persons with AMD, oral supplementation with LCPUFAs or lutein/zeaxanthin had no statistically significant effect on cognitive function. TRIAL REGISTRATION:  clinicaltrials.gov Identifier: NCT00345176.


 

Intake of flavonoids and risk of dementia.
            (Commenges et al., 2000)  Download
It has been postulated that oxidative stress may play a key role in dementia. This is substantiated by the recent discovery of the protective effect of wine. In wine, the flavonoids--powerful antioxidant substances also contained in tea, fruits and vegetables--have been thought to offer such protection. We investigated whether flavonoid intake could be associated with a lower incidence of dementia in a cohort of 1367 subjects above 65 years of age (Paquid). A questionnaire was used to evaluate their intake of flavonoids and subjects were followed-up for 5 years between 1991 and 1996: 66 incident cases of dementia were observed. We estimated the relative risk (RR) of dementia according to tertiles of flavonoid intake using a Cox model. The age-adjusted RR of dementia was 0.55 for the two highest tertiles compared to the lowest (95% CI: 0.34-0.90; p = 0.02). After additional adjustment for gender, education, weight and vitamin C intake, the RR was 0.49 (95% CI: 0.26-0.92; p = 0.04). We conclude that the intake of antioxidant flavonoids is inversely related to the risk of incident dementia.

Fatty acid analysis of blood plasma of patients with Alzheimer's disease, other types of dementia, and cognitive impairment.
            (Conquer et al., 2000)  Download
Fatty acid differences, including docosahexaenoic acid (DHA; 22:6n-3) have been shown in the brains of Alzheimer's patients (AD) as compared with normal age-matched individuals. Furthermore, low serum DHA is a significant risk factor for the development of AD. The relative concentration of DHA and other fatty acids, however, in the plasma of AD patients compared with patients with other kinds of dementias (other dementias; OD), patients who are cognitively impaired but nondemented (CIND), or normal patients is not known. In this study we analyzed the total phospholipid, phosphatidylcholine (PC), phosphatidylethanolamine (PE), and lysophosphatidylcholine (lysoPC) fractions of plasma from patients diagnosed with AD, OD, or CIND and compared them with a group of elderly control subjects with normal cognitive functioning. Plasma phospholipid and PC levels of 20:5n-3, DHA, total n-3 fatty acids, and the n-3/n-6 ratio were lower in the AD, OD, and CIND groups. Plasma phospholipid 24:0 was lower in the AD, OD, and CIND groups as compared with the group of control patients, and total n-6 fatty acid levels were higher in the AD and CIND groups only. In the plasma PE fraction, levels of 20:5n-3, DHA, and the total n-3 fatty acid levels were significantly lower in the AD, OD, and CIND groups. DHA levels were lower in the lysoPC fraction of CIND individuals only. There were no other differences in the fatty acid compositions of the different phospholipid fractions. Therefore, in AD, OD, and CIND individuals, low levels of n-3 fatty acids in the plasma may be a risk factor for cognitive impairment and/or dementia. Interestingly, a decreased level of plasma DHA was not limited to the AD patients but appears to be common in cognitive impairment with aging.

 

The zinc dyshomeostasis hypothesis of Alzheimer's disease
            (Craddock et al., 2012)  Download
Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-beta protein (Abeta), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Abeta accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Abeta and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Abeta-amyloid deposits (Abeta oligomers and plaques) not only drives Abeta aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Abeta deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Abeta amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on beta-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.


 

Silicon-rich mineral water as a non-invasive test of the 'aluminum hypothesis' in Alzheimer's disease.
            (Davenward et al., 2013)  Download
There has been a plausible link between human exposure to aluminum and Alzheimer's disease for several decades. We contend that the only direct and ethically acceptable experimental test of the 'aluminum hypothesis', which would provide unequivocal data specific to the link, is to test the null hypothesis that a reduction in the body burden of aluminum to its lowest practical limit would have no influence upon the incidence, progression, or severity of Alzheimer's disease. Herein we are testing the hypothesis that silicon-rich mineral waters can be used as non-invasive methods to reduce the body burden of aluminum in individuals with Alzheimer's disease and a control group consisting of their carers and partners. We have shown that drinking up to 1 L of a silicon-rich mineral water each day for 12 weeks facilitated the removal of aluminum via the urine in both patient and control groups without any concomitant affect upon the urinary excretion of the essential metals, iron and copper. We have provided preliminary evidence that over 12 weeks of silicon-rich mineral water therapy the body burden of aluminum fell in individuals with Alzheimer's disease and, concomitantly, cognitive performance showed clinically relevant improvements in at least 3 out of 15 individuals. This is a first step in a much needed rigorous test of the 'aluminum hypothesis of Alzheimer's disease' and a longer term study involving many more individuals is now warranted.

Propagation of tau pathology in a model of early Alzheimer's disease.
            (de Calignon et al., 2012)  Download
Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.


 

Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer's disease animal model.
            (Dhanasekaran et al., 2009) Download
PSAPP mice expressing the 'Swedish' amyloid precursor protein and the M146L presenilin 1 mutations are a well-characterized model for spontaneous amyloid beta plaque formation. Centella asiatica has a long history of use in India as a memory enhancing drug in Ayurvedic literature. The study investigated whether Centella asiatica extract (CaE) can alter the amyloid pathology in PSAPP mice by administering CaE (2.5 or 5.0 g/kg/day) starting at 2 months of age prior to the onset of detectable amyloid deposition and continued for either 2 months or 8 months. A significant decrease in amyloid beta 1-40 and 1-42 was detectable by ELISA following an 8 month treatment with 2.5 mg/kg of CaE. A reduction in Congo Red stained fibrillar amyloid plaques was detected with the 5.0 mg/kg CaE dose and long-term treatment regimen. It was also confirmed that CaE functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation and protecting against DNA damage. The data indicate that CaE can impact the amyloid cascade altering amyloid beta pathology in the brains of PSAPP mice and modulating components of the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimer's disease.

A molecular link between the active component of marijuana and Alzheimer's disease pathology
            (Eubanks et al., 2006)  Download
Alzheimer's disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer's disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients and reduce the health care costs attributable to Alzheimer's disease. Here, we demonstrate that the active component of marijuana, Delta9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid beta-peptide (Abeta) aggregation, the key pathological marker of Alzheimer's disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Abeta aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.


 

Pathogenic microbes, the microbiome, and Alzheimer's disease (AD).
            (Hill et al., 2014)  Download
Taken together, it is clear that the human CNS is under constant assault by a wide array of extrinsic and intrinsic neurotrophic microbes and pathogens including bacteria, virus, fungus, nucleic-acid free prions, or small non-coding RNAs found both in the environment and contained within the microbiome. Virtually every type of microbe known has been implicated in contributing to the suscepti- bility and pathogenesis of the AD process.

Herpes simplex virus type 1 and Alzheimer's disease: increasing evidence for a major role of the virus.
            (Itzhaki, 2014)  Download
Herpes simplex virus type 1 (HSV1), when present in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE), has been implicated as a major factor in Alzheimer's disease (AD). It is proposed that virus is normally latent in many elderly brains but reactivates periodically (as in the peripheral nervous system) under certain conditions, for example stress, immunosuppression, and peripheral infection, causing cumulative damage and eventually development of AD. Diverse approaches have provided data that explicitly support, directly or indirectly, these concepts. Several have confirmed HSV1 DNA presence in human brains, and the HSV1-APOE-ε4 association in AD. Further, studies on HSV1-infected APOE-transgenic mice have shown that APOE-e4 animals display a greater potential for viral damage. Reactivated HSV1 can cause direct and inflammatory damage, probably involving increased formation of beta amyloid (Aβ) and of AD-like tau (P-tau)-changes found to occur in HSV1-infected cell cultures. Implicating HSV1 further in AD is the discovery that HSV1 DNA is specifically localized in amyloid plaques in AD. Other relevant, harmful effects of infection include the following: dynamic interactions between HSV1 and amyloid precursor protein (APP), which would affect both viral and APP transport; induction of toll-like receptors (TLRs) in HSV1-infected astrocyte cultures, which has been linked to the likely effects of reactivation of the virus in brain. Several epidemiological studies have shown, using serological data, an association between systemic infections and cognitive decline, with HSV1 particularly implicated. Genetic studies too have linked various pathways in AD with those occurring on HSV1 infection. In relation to the potential usage of antivirals to treat AD patients, acyclovir (ACV) is effective in reducing HSV1-induced AD-like changes in cell cultures, and valacyclovir, the bioactive form of ACV, might be most effective if combined with an antiviral that acts by a different mechanism, such as intravenous immunoglobulin (IVIG).


 

Common mechanisms involved in Alzheimer's disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation.
            (Miklossy and McGeer, 2016)  Download
Strong epidemiologic evidence and common molecular mechanisms support an association between Alzheimer's disease (AD) and type 2-diabetes. Local inflammation and amyloidosis occur in both diseases and are associated with periodontitis and various infectious agents. This article reviews the evidence for the presence of local inflammation and bacteria in type 2 diabetes and discusses host pathogen interactions in chronic inflammatory disorders. Chlamydophyla pneumoniae, Helicobacter pylori and spirochetes are demonstrated in association with dementia and brain lesions in AD and islet lesions in type 2 diabetes. The presence of pathogens in host tissues activates immune responses through Toll-like receptor signaling pathways. Evasion of pathogens from complement-mediated attack results in persistent infection, inflammation and amyloidosis. Amyloid beta and the pancreatic amyloid called amylin bind to lipid bilayers and produce Ca(2+) influx and bacteriolysis. Similarly to AD, accumulation of amylin deposits in type 2 diabetes may result from an innate immune response to chronic bacterial infections, which are known to be associated with amyloidosis. Further research based on an infectious origin of both AD and type 2 diabetes may lead to novel treatment strategies.

Zinc homeostasis and neurodegenerative disorders
            (Szewczyk, 2013)  Download
Zinc is an essential trace element, whose importance to the function of the central nervous system (CNS) is increasingly being appreciated. Alterations in zinc dyshomeostasis has been suggested as a key factor in the development of several neuropsychiatric disorders. In the CNS, zinc occurs in two forms: the first being tightly bound to proteins and, secondly, the free, cytoplasmic, or extracellular form found in presynaptic vesicles. Under normal conditions, zinc released from the synaptic vesicles modulates both ionotropic and metabotropic post-synaptic receptors. While under clinical conditions such as traumatic brain injury, stroke or epilepsy, the excess influx of zinc into neurons has been found to result in neurotoxicity and damage to postsynaptic neurons. On the other hand, a growing body of evidence suggests that a deficiency, rather than an excess, of zinc leads to an increased risk for the development of neurological disorders. Indeed, zinc deficiency has been shown to affect neurogenesis and increase neuronal apoptosis, which can lead to learning and memory deficits. Altered zinc homeostasis is also suggested as a risk factor for depression, Alzheimer's disease (AD), aging, and other neurodegenerative disorders. Under normal CNS physiology, homeostatic controls are put in place to avoid the accumulation of excess zinc or its deficiency. This cellular zinc homeostasis results from the actions of a coordinated regulation effected by different proteins involved in the uptake, excretion and intracellular storage/trafficking of zinc. These proteins include membranous transporters (ZnT and Zip) and metallothioneins (MT) which control intracellular zinc levels. Interestingly, alterations in ZnT and MT have been recently reported in both aging and AD. This paper provides an overview of both clinical and experimental evidence that implicates a dysfunction in zinc homeostasis in the pathophysiology of depression, AD, and aging.

In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease.
            (Watt and Karl, 2017)  Download
Alzheimer's disease (AD) is a debilitating neurodegenerative disease that is affecting an increasing number of people. It is characterized by the accumulation of amyloid-β and tau hyperphosphorylation as well as neuroinflammation and oxidative stress. Current AD treatments do not stop or reverse the disease progression, highlighting the need for new, more effective therapeutics. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has demonstrated neuroprotective, anti-inflammatory and antioxidant properties in vitro. Thus, it is investigated as a potential multifunctional treatment option for AD. Here, we summarize the current status quo of in vivo effects of CBD in established pharmacological and transgenic animal models for AD. The studies demonstrate the ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as to promote neurogenesis. Importantly, CBD also reverses and prevents the development of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD and Δ(9)-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone. The studies provide "proof of principle" that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies. Further investigations should address the long-term potential of CBD and evaluate mechanisms involved in the therapeutic effects described.


 

References

Ahmed, A, et al. (2015), ‘Cannabinoids in late-onset Alzheimer’s disease.’, Clin Pharmacol Ther, 97 (6), 597-606. PubMed: 25788394
Brewer, G. J. and S. Kaur (2013), ‘Zinc Deficiency and Zinc Therapy Efficacy with Reduction of Serum Free Copper in Alzheimer’s Disease’, Int J Alzheimers Dis, 2013 586365. PubMed: 24224111
Chew, EY, et al. (2015), ‘Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial.’, JAMA, 314 (8), 791-801. PubMed: 26305649
Commenges, D, et al. (2000), ‘Intake of flavonoids and risk of dementia.’, Eur J Epidemiol, 16 (4), 357-63. PubMed: 10959944
Conquer, JA, et al. (2000), ‘Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment.’, Lipids, 35 (12), 1305-12. PubMed: 11201991
Craddock, T. J., et al. (2012), ‘The zinc dyshomeostasis hypothesis of Alzheimer’s disease’, PLoS One, 7 (3), e33552. PubMed: 22457776
Davenward, S, et al. (2013), ‘Silicon-rich mineral water as a non-invasive test of the ‘aluminum hypothesis’ in Alzheimer’s disease.’, J Alzheimers Dis, 33 (2), 423-30. PubMed: 22976072
de Calignon, A, et al. (2012), ‘Propagation of tau pathology in a model of early Alzheimer’s disease.’, Neuron, 73 (4), 685-97. PubMed: 22365544
Dhanasekaran, M, et al. (2009), ‘Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer’s disease animal model.’, Phytother Res, 23 (1), 14-19. PubMed: 19048607
Eubanks, L. M., et al. (2006), ‘A molecular link between the active component of marijuana and Alzheimer’s disease pathology’, Mol Pharm, 3 (6), 773-77. PubMed: 17140265
Hill, JM, et al. (2014), ‘Pathogenic microbes, the microbiome, and Alzheimer’s disease (AD).’, Front Aging Neurosci, 6 127. PubMed: 24982633
Itzhaki, RF (2014), ‘yHerpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus.’, Front Aging Neurosci, 6 202. PubMed: 25157230
Miklossy, J and PL McGeer (2016), ‘Common mechanisms involved in Alzheimer’s disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation.’, Aging (Albany NY), PubMed: 26961231
Szewczyk, B. (2013), ‘Zinc homeostasis and neurodegenerative disorders’, Front Aging Neurosci, 5 33. PubMed: 23882214
Watt, G and T Karl (2017), ‘In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer’s Disease.’, Front Pharmacol, 8 20. PubMed: 28217094