Metal-catalyzed oxidative damage and oligomerization of the amyloid-β peptide of Alzheimer’s disease

The most common form of dementia in old age is Alzheimer’s disease (AD). The presence in the brain of senile plaque is the major pathological marker of AD. The plaques are primarily composed of aggregated amyloid-β peptide (Aβ). Aβ is a 40–42 amino acid peptide that is a proteolytic product derived from the β-amyloid precursor protein. The function of Aβ and the exact mechanism of Aβ aggregation and neurotoxicity are unclear. However, metal coordination by Aβ plays an important role in inducing aggregation and the generation of reactive oxygen species, which appears to be at least partially responsible for Aβ neurotoxicity. In this review we examine the role of copper and zinc ions in Aβ neurotoxicity, especially with regards to the generation of free radicals. We discuss the role of copper or zinc ions in oxidative damage and Aβ conformational changes and the relationship of these metals to AD.

Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimers disease, across the blood-brain

Cryptotanshinone (CTS), a major constituent from the roots of Salvia miltiorrhiza (Danshen), is widely used in the treatment of coronary heart disease, stroke and less commonly Alzheimer's disease. Our recent study indicates that CTS is a substrate for Pglycoprotein (PgP/MDR1/ABCB1). This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models. A polarized transport of CTS was found in rat primary microvascular endothelial cell (RBMVEC) monolayers, with facilitated efflux from the abluminal side to luminal side. Addition of a PgP (e.g. verapamil and quinidine) or multi-drug resistance protein 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake of CTS into the cerebrum increased from 0.52 ± 0.1% at 1 min to 11.13 ± 2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose. Co-perfusion of a PgP/MDR1 (e.g. verapamil) or MRP1/2 inhibitor (e.g. probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21% of those in plasma, and were significantly increased when coadministered with verapamil or probenecid in rats. The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid (a neurotoxin) were about 2- to 2.5-fold higher than the control rats. Moreover, the brain levels in mdr1a(-/-) and mrp1(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice, respectively. Taken collectively, these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents, suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1. Further studies are needed to explore the role of other drug transporters in restricting the brain penetration of CTS and the clinical relevance.

Associations between DNA damage, DNA base excision repair gene variability and Alzheimer's disease risk

BACKGROUND: Increased oxidative damage to DNA is one of the pathways involved in Alzheimer's disease (AD). Insufficient base excision repair (BER) is in part responsible for increased oxidative DNA damage. The aim of the present study was to assess the effect of polymorphic variants of BER-involved genes and the peripheral markers of DNA damage and repair in patients with AD. MATERIAL AND METHODS: Comet assays and TaqMan probes were used to assess DNA damage, BER efxFB01;ciency and polymorphic variants of 12 BER genes in blood samples from 105 AD patients and 130 controls. The DNA repair efficacy (DRE) was calculated according to a specific equation. RESULTS: The levels of endogenous and oxidative DNA damages were higher in AD patients than controls. The polymorphic variants of XRCC1 c.580C>T XRCC1 c.1196A>G and OGG1 c.977C>G are associated with increased DNA damage in AD. CONCLUSION: Our results show that oxidative stress and disturbances in DRE are particularly responsible for the elevated DNA lesions in AD. The results suggest that oxidative stress and disruption in DNA repair may contribute to increased DNA damage in AD patients and risk of this disease. In addition, disturbances in DRE may be associated with polymorphisms of OGG1 and XRCC1.

A brief introduction to the history of the ß-amyloid protein (Aß) of Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Typically, the disease progresses in a prolonged, inexorable manner [1]. Patients initially show symptoms of mild cognitive impairment, which may include some memory loss. As the disease progresses, more severe memory loss occurs (e.g., retrograde amnesia) leading to confusion and lack of orientation. The patient is often institutionalized in this period, as it becomes increasingly difficult for family members to cope with the constant requirements of care. In later stages of the disease, apathy and stupor can occur, and the patient becomes bedridden.

Amyloid-beta and depression in healthy older adults: a systematic review

Depression has been shown to be a risk factor for Alzheimer's disease (AD), and in older adults may provide a marker for the beginning of the prodromal phase of AD. The purpose of this systematic review is to examine the relationship between amyloid-β (Aβ), a key biomarker of AD, and depression in older adults.

The effects of multivitamins on cognitive performance: a systematic review and meta-analysis

Complementary medicine use is becoming increasingly popular with multivitamins being the most commonly used vitamin supplement. Although adequate vitamin and nutrient concentrations are necessary for optimal health and cognitive functioning, there is no scientific consensus as to whether multivitamin use prevents cognitive decline or improves mental functioning. The aim of the present study was to determine if multivitamins can be used efficaciously to improve cognitive abilities. A systematic review of randomized controlled trials was performed. Meta-analysis was performed on those cognitive tests used across the largest number of studies. Multiple electronic databases were searched until July 2011 by two authors. Randomized, placebo-controlled trials were considered appropriate if they reported on the chronic effects (≥1 month) of oral multivitamin supplementation on any valid cognitive outcomes. Ten trials were included in review (n = 3,200). Meta-analysis indicated that multivitamins were effective in improving immediate free recall memory (SMD = 0.32; 95% CI: 0.09-0.56, p < 0.01) but not delayed free recall memory (SMD = -0.14; 95% CI: -0.43-0.14, p = 0.33) or verbal fluency (SMD = 0.06; 95% CI: -0.05-0.18, p = 0.26). There was no evidence of publication bias or heterogeneity. Other cognitive abilities sensitive to AD pathology, such as executive and visuospatial functions, were found to be under researched. In conclusion, multivitamins were found to enhance immediate free recall memory but no other cognitive domains.

Amyloid peptide self assembly in protic ionic liquids

Overall, this thesis presents the novel approach of using carefully selected PILs to both control amyloid fibril formation and inhibit/dissolve Aβ fibrils through induced helical transitions. These results provide insights into future PIL-mediated protein studies and the potential application of PILs in AD pathogenesis.

Uptake of a newly implemented advance care planning program in a dementia diagnostic service

BACKGROUND: advance care planning (ACP) provides a framework for discussion and documentation of future care preferences when a person loses cognitive capacity. It can assist people in the early stages of dementia to document their preferences for care at later stages of the illness. METHOD: a three-stage project introduced ACP to clients with mild cognitive impairment (MCI) or recently diagnosed dementia and their families through a specialist memory clinic. Over 8 months, all English-speaking clients (n = 97) and carers (n = 92) were mailed a survey assessing completed documentation for future care; understanding of the principles of ACP and willingness to get further information about ACP (Stage 1). Participants wanting more information were invited to a seminar introducing the ACP program and service (Stage 2). Participants wanting to complete ACP documentation could make an appointment with the ACP clinicians (Stage 3). RESULTS: forty-eight (52.2%) carers and 34 clients (35.1%) responded to the survey. Most clients (62.1%) and carers (79.1%) expressed interest in ACP, and 78.6% of clients and 63.6% of carers believed that clients should be involved in their future medical decisions. Nine clients (26.5%; diagnoses: MCI = 5; AD = 3; mixed dementia = 1) and 9 carers (18.8%) attended the seminars, and 2/48 (4%) carers and 3/34 (8.8%) clients (diagnoses: MCI = 2; AD = 1) completed ACP. CONCLUSION: despite initial interest, ACP completion was low. The reasons for this need to be determined. Approaches that may better meet the needs of people newly diagnosed with MCI and dementia are discussed.

Lipids in Amyloid-β processing, aggregation, and toxicity

Aggregation of amyloid-beta (Aβ) peptide is the major event underlying neuronal damage in Alzheimer's disease (AD). Specific lipids and their homeostasis play important roles in this and other neurodegenerative disorders. The complex interplay between the lipids and the generation, clearance or deposition of Aβ has been intensively investigated and is reviewed in this chapter. Membrane lipids can have an important influence on the biogenesis of Aβ from its precursor protein. In particular, increased cholesterol in the plasma membrane augments Aβ generation and shows a strong positive correlation with AD progression. Furthermore, apolipoprotein E, which transports cholesterol in the cerebrospinal fluid and is known to interact with Aβ or compete with it for the lipoprotein receptor binding, significantly influences Aβ clearance in an isoform-specific manner and is the major genetic risk factor for AD. Aβ is an amphiphilic peptide that interacts with various lipids, proteins and their assemblies, which can lead to variation in Aβ aggregation in vitro and in vivo. Upon interaction with the lipid raft components, such as cholesterol, gangliosides and phospholipids, Aβ can aggregate on the cell membrane and thereby disrupt it, perhaps by forming channel-like pores. This leads to perturbed cellular calcium homeostasis, suggesting that Aβ-lipid interactions at the cell membrane probably trigger the neurotoxic cascade in AD. Here, we overview the roles of specific lipids, lipid assemblies and apolipoprotein E in Aβ processing, clearance and aggregation, and discuss the contribution of these factors to the neurotoxicity in AD.

Links between copper and cholesterol in Alzheimer's disease

Altered copper homeostasis and hypercholesterolemia have been identified independently as risk factors for Alzheimer's disease (AD). Abnormal copper and cholesterol metabolism are implicated in the genesis of amyloid plaques and neurofibrillary tangles (NFT), which are two key pathological signatures of AD. Amyloidogenic processing of a sub-population of amyloid precursor protein (APP) that produces Aβ occurs in cholesterol-rich lipid rafts in copper deficient AD brains. Co-localization of Aβ and a paradoxical high concentration of copper in lipid rafts fosters the formation of neurotoxic Aβ:copper complexes. These complexes can catalytically oxidize cholesterol to generate H2O2, oxysterols and other lipid peroxidation products that accumulate in brains of AD cases and transgenic mouse models. Tau, the core protein component of NFTs, is sensitive to interactions with copper and cholesterol, which trigger a cascade of hyperphosphorylation and aggregation preceding the generation of NFTs. Here we present an overview of copper and cholesterol metabolism in the brain, and how their integrated failure contributes to development of AD.

Copper in disorders with neurological symptoms: Alzheimer`s, Menkes, and Wilson Diseases

Copper is an essential element for the activity of a number of physiologically important enzymes. Enzyme-related malfunctions may contribute to severe neurological symptoms and neurological diseases: copper is a component of cytochrome c oxidase, which catalyzes the reduction of oxygen to water, the essential step in cellular respiration. Copper is a cofactor of Cu/Zn-superoxide-dismutase which plays a key role in the cellular response to oxidative stress by scavenging reactive oxygen species. Furthermore, copper is a constituent of dopamine-β-hydroxylase, a critical enzyme in the catecholamine biosynthetic pathway. A detailed exploration of the biological importance and functional properties of proteins associated with neurological symptoms will have an important impact on understanding disease mechanisms and may accelerate development and testing of new therapeutic approaches. Copper binding proteins play important roles in the establishment and maintenance of metal-ion homeostasis, in deficiency disorders with neurological symptoms (Menkes disease, Wilson disease) and in neurodegenerative diseases (Alzheimer’s disease). The Menkes and Wilson proteins have been characterized as copper transporters and the amyloid precursor protein (APP) of Alzheimer’s disease has been proposed to work as a Cu(II) and/or Zn(II) transporter. Experimental, clinical and epidemiological observations in neurodegenerative disorders like Alzheimer’s disease and in the genetically inherited copper-dependent disorders Menkes and Wilson disease are summarized. This could provide a rationale for a link between severely dysregulated metal-ion homeostasis and the selective neuronal pathology.

Dimerisation of N-acetyl-L-tyrosine ethyl ester and Aß peptides via formation of dityrosine

Alzheimer's disease (AD) is characterised by the formation of amyloid deposits composed primarily of the amyloid β-peptide (Aβ). This peptide has been shown to bind redox active metals ions such as copper and iron, leading to the production of reactive oxygen species (ROS) and formation of hydrogen peroxide (H2O2). The generation of H2O2 has been linked with Aβ neurotoxicity and neurodegeneration in AD. Because of the relative stability of a tyrosyl radical, the tyrosine residue (Tyr-10) is believed to be critical to the neurotoxicity of Aβ. This residue has also been shown to be important to Aβ aggregation and amyloid formation. It is possible that the formation of an Aβ tyrosyl radical leads to increased aggregation via the formation of dityrosine as an early aggregation step, which is supported by the identification of dityrosine in amyloid plaque. The role of dityrosine formation in Aβ aggregation and neurotoxicity is as yet undetermined, partly because there are no facile methods for the synthesis of Aβ dimers containing dityrosine. Here we report the use of horseradish peroxidase and H2O2 to dimerise N-acetyl-l-tyrosine ethyl ester and apply the optimised conditions for dityrosine formation to fully unprotected Aβ peptides. We also report a simple fluorescent plate reader method for monitoring Aβ dimerisation via dityrosine formation.

Methionine regulates copper/hydrogen peroxide oxidation products of Aβ

Metal-catalysed oxidation (MCO) may play a causative role in the pathogenesis of Alzheimer's disease (AD). Amyloid peptide (A), the major biomarker of AD, in the presence of copper ions reduces Cu2+ to Cu+ and catalyses the formation of H2O2 that subsequently induces radicals through Fenton chemistry. A is also subject to attack by free radicals, where the presence of Cu2+ in conjunction with H2O2 catalyses oxygenation, primarily at the methionine sulfur atom. This work investigates MCO of A, to gain further insight into the role of oxidative stress in AD. By combining a fluorescence assay with gel electrophoresis to monitor MCO reactions of A (1-28) in the presence and absence of methionine it was determined that methionine can both protect some residues against MCO and promote the oxidation of Tyr(10) specifically. Electrospray ionization mass spectrometric analysis of methionine MCO products indicated the formation of methionine sulfoxide, methionine sulfone and related hydroxylated products. Similar products could be formed from the oxidation of Met(35) of A and may relate to changes in properties of the peptide following MCO.

A cetylcholinesterase is increased in mouse neuronal and astrocyte cultures after treatment with b-amyloid peptides

The cellular origin of the acetylcholinesterase (AChE) associated with amyloid plaques in the Alzheimer’s disease (AD) brain is unknown. In this study we report that amyloid β-peptides (Aβ) increased AChE levels in both neuronal and astrocytic primary cultures, supporting the possibility that both neurons and glia may make a direct contribution to the pool of AChE seen around amyloid deposits in the AD brain.