A standard model of Alzheimer’s disease?

ABSTRACT

The recent Research Framework proposed by the US National Institute on Aging and the Alzheimer’s Association (NIA-AA) recommends that Alzheimer’s disease be defined by its specific biology rather than by non-specific neurodegenerative and syndromal features. By affirming markers of abnormal Aβ and tau proteins as the essential pathobiological signature of Alzheimer’s disease, the Framework tacitly reinforces the amyloid (Aβ) cascade as the leading theory of Alzheimer pathogenesis. In light of recent evidence that the cascade is driven by the misfolding and templated aggregation of Aβ and tau, we believe that an empirically grounded Standard Model of Alzheimer’s pathogenesis is within reach. A Standard Model can clarify and consolidate existing information, contextualize risk factors and the complex disease phenotype, identify testable hypotheses for future research, and pave the most direct path to effective prevention and treatment.     

Alzheimer disease and platelets: how’s that relevant

Alzheimer Disease (AD) is the most common neurodegenerative disorder worldwide, and account for 60% to 70% of all cases of progressive cognitive impairment in elderly patients. At the microscopic level distinctive features of AD are neurons and synapses degeneration, together with extensive amounts of senile plaques and neurofibrillars tangles. The degenerative process probably starts 20–30 years before the clinical onset of the disease. Senile plaques are composed of a central core of amyloid β peptide, Aβ, derived from the metabolism of the larger amyloid precursor protein, APP, which is expressed not only in the brain, but even in non neuronal tissues. More than 30 years ago, some studies reported that human platelets express APP and all the enzymatic activities necessary to process this protein through the same pathways described in the brain. Since then a large number of evidence has been accumulated to suggest that platelets may be a good peripheral model to study the metabolism of APP, and the pathophysiology of the onset of AD. In this review, we will summarize the current knowledge on the involvement of platelets in Alzheimer Disease. Although platelets are generally accepted as a suitable model for AD, the current scientific interest on this model is very high, because many concepts still remain debated and controversial. At the same time, however, these still unsolved divergences mirror a difficulty to establish constant parameters to better defined the role of platelets in AD.     

Decrease of dynamin 2 levels in late-onset Alzheimer’s disease alters Aβ metabolism

Late-onset Alzheimer’s disease (LOAD) is significantly associated with a single nucleotide polymorphism located in the dynamin (DNM) 2 gene, especially in non-carriers of the apolipoprotein E-ε4 allele. In this study we used real-time PCR to show that DNM2 mRNA is significantly reduced in the cortex of AD brains and in the peripheral blood of dementia patients. Neuroblastoma cells transfected with a dominant negative DNM2 had increased amyloid beta protein (Aβ) secretion and most of the amyloid precursor protein (APP) in these cells was localized to the plasma membrane. In addition, these cells were rich in flotillin, which is a component of lipid rafts. These data suggest that DNM2 expression is reduced in LOAD, which results in the accumulation of APP in lipid raft-rich plasma membranes. Consequently, Aβ secretion may increase in LOAD neurons.     

A brief overview of amyloids and Alzheimer’s disease

Amyloid fibrils are self-assembled fibrous protein aggregates that are associated with a number of presently incurable diseases such as Alzheimer’s and Parkinson’s disease. Millions of people worldwide suffer from amyloid diseases. This review summarizes the unique cross-β structure of amyloid fibrils, morphological variations, the kinetics of amyloid fibril formation, and the cytotoxic effects of these fibrils and oligomers. Alzheimer’s disease is also explored as an example of an amyloid disease to show the various approaches to treat these amyloid diseases. Finally, this review investigates the nanotechnological and biological applications of amyloid fibrils; as well as a summary of the typical biological pathways involved in the disposal of amyloid fibrils and their precursors.     

Amyloid beta–heme peroxidase promoted protein nitrotyrosination: relevance to widespread protein nitration in Alzheimer’s disease

Amyloid beta (Aβ) peptide accumulation has been demonstrated to play a central role in Alzheimer’s disease (AD). Substantial evidence indicates that protein nitrotyrosination contributes to Aβ-dependent neurotoxicity; however, the molecular mechanism is unknown. Recent research has shown that Aβ complexes with heme to form Aβ–heme, and increases the pseudo-peroxidase activity of heme. We found that Aβ–heme uses H₂O₂ and NO₂ ⁻ to cause nitration of enolase and synaptic proteins more effectively than heme. Thus, the increased peroxidase activity of Aβ–heme may be the molecular link between excess Aβ and the widespread protein nitration in AD. Interestingly, the site of enolase nitration that was catalyzed by Aβ–heme is different from that induced by heme. Moreover, the secondary structural perturbations of Aβ–heme-treated and heme-treated enolase are also different. These observations suggest that Aβ–heme targets specific amino acid sequences in enolase. Furthermore, our data show that Aβ–heme peroxidase activity is independent of the aggregation state of Aβ, suggesting an important role of soluble Aβ in addition to Aβ aggregates and oligomers in AD pathogenesis.     

A 50-year perspective of a family with chromosome-14-linked Alzheimer’s disease

A Swedish family with two generations suffering from presenile dementia with an unusually severe Alzheimer encephalopathy was first reported in 1946. The hypothesis that the disease was inherited through a dominant gene is strongly supported by the follow-up 50years later of three additional generations and molecular genetic findings of a novel presenilin-1 gene mutation in the family. The pedigree contains six cases with well-documented dementia in four consecutive generations. The Alzheimer encephalopathy was unusually severe in the three cases studied post-mortem, with a pronounced involvement of the central grey structures, such as the claustrum, the nuclei around the third ventricle, the central thalamic nuclei and the brain stem. There were no vascular lesions and little amyloid angiopathy. All six affected cases showed the typical temporoparietal symptom pattern and other core symptoms of Alzheimer’s disease, such as logoclonia, myoclonic twitchings and major motor seizures. Other predominant features were psychomotor slowness, increased muscular tension, a stiff stooped gait and a rapid loss of weight. The symptom pattern is convincingly explained by the consistent and severe involvement of cortical and central grey structures and is probably linked to the presenilin-1 gene mutation. Received: 25 November 1997 / Accepted 4 December 1997     

Neurotoxicity in Alzheimer’s disease: is covalently crosslinked Aβ responsible?

Alzheimer’s disease is the most common form of dementia in the elderly, and is characterised by extracellular amyloid plaques composed of the β-amyloid peptide (Aβ). However, disease progression has been shown to correlate more closely with the level of soluble Aβ oligomers. Recent evidence suggests that these oligomers are covalently crosslinked, possibly due to the interaction of Aβ with redox-active metal ions. These findings offer new avenues for the treatment and prevention of disease, by modulating metal binding or preventing the formation of neurotoxic Aβ oligomers. Australian Society for Biophysics Special Issue: Metals and Membranes in Neuroscience.     

Exploring glia to better understand Alzheimer’s disease

The amyloid-β (Aβ) hypothesis has been the leading explanation for the pathogenesis of Alzheimer’s disease (AD). The most common traits of AD are cognitive impairments and memory loss, which are associated with the accumulation of Aβ. Aβ aggregates activate glial cells, which in turn remove Aβ. Because microglia act as immune cells in the brain, most glia-related studies of AD have focused primarily on this cell type. However, astrocytes, another type of glial cell, also participate in the brain immune system, synaptic formation, brain homeostasis, and various other brain functions. Accordingly, many studies on the underlying mechanisms of AD have investigated not only neurons but also glial cells. Although these studies suggest that microglia and astrocytes are effective targets for AD therapeutics, other recent studies have raised questions regarding whether microglial cells and/or astrocytes serve a neuroprotective or neurotoxic function in AD. To gain a better understanding of the mechanisms of AD and identify novel targets for AD treatment, in this review, we consider the role of both microglia and astrocytes in AD.     

Evolution of Alzheimer’s disease pathogenesis conception

Alzheimer’s disease (AD) is a neurodegenerative disorder that becomes a cause of dementia during atrophic brain changes. There are two distinguished forms of AD: familial early-onset form (FAD, approximately 5% of all cases, develops before age 65, most commonly 40–50) and sporadic late-onset form (SAD, approximately 95% of all cases, develops after 65). Identification of genetic determinants of FAD development and evidence of amyloid-beta peptide’s (Aβ) neurotoxicity as a central event in the cascade of pathological processes significantly expanded the conception of molecular and genetic mechanisms of the disease. However, the question of whether or not the accumulation of Aβ is the triggering factor of more widespread SAD remains open. There are a growing number of arguments for Aβ overproduction being the secondary, concomitant event of AD pathological processes: synaptic failure, hyperphosphorylation of tau protein, neuroinflammation, neuronal loss, and cognitive decline. As one of triggering risk factors of AD development, mitochondrial dysfunction is considered, with the decrease in ATP synthesis and oxidative stress becoming the consequences. However, the specific molecular and genetic mechanisms of AD remain unclear. This is caused by the lack of relevant animal models for studying mechanisms of the disease and objective estimation of pathogenically justified methods of AD prevention and treatment.     

The study of Alzheimer’s disease biomarkers

Alzheimer’s disease (AD) is by far the most common dementing illness of late life and is increasing with the ever-growing number of older adults, in particular, in developed countries. The disease is often referred to as the “Long-Goodbye” because the person with the illness slowly becomes lost to everyone a long time before the body finally gives out. Being able to detect AD earlier on during the course of the disease offers better prospects for the future, for AD individuals, their families and friends as well as on the economy, as a whole. Unfortunately, such a detection technique is not yet, available. However, there are a number of promising biological markers (biomarkers) that correlate well with clinical cognitive tests of individuals and/or postmortem histopathological manifestations of the disease, especially when at least two markers are used for the diagnosis. Biosensors are tools that combine a biochemical binding element to a signal conversion unit and are already being used in the study of some AD biomarkers. However, their use in clinical diagnosis remains a challenge. Introduction of nanotechnology leading to nanobiosensors has several potential advantages over other clinical and/or existing analytical tools, including increased assay speed, flexibility, reduced cost of diagnostic testing, potential to deliver molecular diagnostic tools to family general practitioners, and other health care systems. Even more important, nano-based assays have the potential to detect target proteins at attomolar concentration level. They are, therefore, being increasingly exploited for the detection of early metabolic changes associated with diseases. Because brain damage is irreversible, the use of nanotechnology is particularly important in AD and other neurodegenerative disorders. Nanosensors can also facilitate and enable pointofcare-testing (POCT). This article reviews the basic biochemical processes that lead to AD pathology, current biomarkers for AD, and the current role of nanosensor technology for the study of AD biomarkers. Furthermore, it discusses the huge potential of nanosensing to deliver new molecular diagnostic strategies to AD research.     

Delineating the Mechanism of Alzheimer’s Disease Aβ Peptide Neurotoxicity

The Alzheimer’s disease neurotoxic amyloid-β (Aβ) peptide is derived from the larger amyloid precursor protein (APP) and is the principal component of the senile plaques in Alzheimer’s disease (AD) brains. This mechanism by which Aβ mediates neurotoxicity or neuronal dysfunction is not fully resolved. This review will outline some of the key determinants that modulate Aβ’s activity and the cellular pathways and mechanisms involved.     

Common variants of ACE contribute to variable age-at-onset of Alzheimer’s disease

Studies on the role that genetic variation may play in a complex human disease can be empowered by an assessment of both disease risk in case-control or family models and of quantitative traits that reflect elements of disease etiology. An excellent example of this can be found for the 4 allele of APOE in relation to Alzheimers disease (AD) for which association with both risk and age-at-onset (AAO) is evident. Following a recent demonstration that variants of the gene encoding angiotensin I converting enzyme (ACE) contribute to AD risk, we have explored the potential influence of ACE upon AAO in AD. A total of 2861 individuals from three European populations, including six independent AD samples, have been examined in this study. Three single nucleotide polymorphisms (SNPs) previously demonstrated to have maximum effects upon ACE plasma levels and that span the ACE locus were genotyped in these materials. A strong effect upon AAO was observed for marker rs4343 in exon 17 (P<0.0001), but evidence was also obtained indicating a possible independent effect of marker rs4291 (P=0.0095) located in the ACE promoter. Effects were consistent with data from previous studies suggesting association with AD in case-control models, whereby alleles demonstrated to confer risk to disease also appear to reduce AAO. Equivalent effects were evident regardless of APOE 4 carrier status and in both males and females. These results provide an important complement to existing AD risk data, confirming that ACE harbors sequence variants that contribute to aspects of AD pathology.     

Cultivable butyrate-producing bacteria of elderly Japanese diagnosed with Alzheimer’s disease

The group of butyrate-producing bacteria within the human gut microbiome may be associated with positive effects on memory improvement, according to previous studies on dementia-associated diseases. Here, fecal samples of four elderly Japanese diagnosed with Alzheimer’s disease (AD) were used to isolate butyrate-producing bacteria. 226 isolates were randomly picked, their 16S rRNA genes were sequenced, and assigned into sixty OTUs (operational taxonomic units) based on BLASTn results. Four isolates with less than 97% homology to known sequences were considered as unique OTUs of potentially butyrate-producing bacteria. In addition, 12 potential butyrate-producing isolates were selected from the remaining 56 OTUs based on scan-searching against the PubMed and the ScienceDirect databases. Those belonged to the phylum Bacteroidetes and to the clostridial clusters I, IV, XI, XV, XIVa within the phylum Firmicutes. 15 out of the 16 isolates were indeed able to produce butyrate in culture as determined by high-performance liquid chromatography with UV detection. Furthermore, encoding genes for butyrate formation in these bacteria were identified by sequencing of degenerately primed PCR products and included the genes for butyrate kinase (buk), butyryl-CoA: acetate CoAtransferase (but), CoA-transferase-related, and propionate CoA-transferase. The results showed that eight isolates possessed buk, while five isolates possessed but. The CoA-transfer-related gene was identified as butyryl-CoA:4-hydroxybutyrate CoA transferase (4-hbt) in four strains. No strains contained the propionate CoA-transferase gene. The biochemical and butyrate-producing pathways analyses of butyrate producers presented in this study may help to characterize the butyrate-producing bacterial community in the gut of AD patients.     

Association of transferrin C2 allele with late-onset Alzheimer’s disease

Transferrin (Tf), an iron-transporting protein, has many variants, but C1 and C2 variants account for the majority of the population in all races. Since Tf is reported to be immunocytochemically detectable in senile plaques in Alzheimer’s disease (AD), we have examined the Tf allele frequency among AD patients. The C2 allele frequency in late-onset AD patients is significantly higher than that in age-matched controls. Unexpectedly, the C2 allele frequency in AD patients homozygous for the ApoE ɛ4 allele is markedly increased, i.e., it is twice as high as that in the remaining AD patients carrying zero or one copy of the ɛ4 allele. Received: 28 May 1997 / Accepted: 7 August 1997     

Pushing the boundaries of brain organoids to study Alzheimer’s disease

Progression of Alzheimer’s disease (AD) entails deterioration or aberrant function of multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell–cell interactions become dysregulated in AD requires novel human cell-based in vitro platforms that could recapitulate the intricate cytoarchitecture and cell diversity of the human brain. Brain organoids (BOs) are 3D self-organizing tissues that partially resemble the human brain architecture and can recapitulate AD-relevant pathology. In this review, we highlight the versatile applications of different types of BOs to model AD pathogenesis, including amyloid-β and tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, and other phenotypes, as well as to accelerate therapeutic development for AD.     

Anti-diabetic vanadyl complexes reduced Alzheimer’s disease pathology independent of amyloid plaque deposition

Association of Alzheimer's disease(AD) with cerebral glucose hypometabolism, likely due to impairments of insulin signaling,has been reported recently, with encouraging results when additional insulin is provided to AD patients. Here, we tested the potential effects of the anti-diabetic vanadium, vanadyl(IV) acetylacetonate(VAC), on AD in vitro and in vivo models. The experimental results showed that VAC at sub-micromolar concentrations improved the viability of neural cells with or without increased β-amyloid(Aβ) burden; and in APP/PS1 transgenic mice, VAC treatment(0.1 mmol kg-1 d-1) preserved cognitive function and attenuated neuron loss, but did not reduce brain Aβ plaques. Further studies revealed that VAC attenuated Aβpathogenesis by(i) activation of the PPARγ-AMPK signal transduction pathway, leading to improved glucose and energy metabolism;(ii) up-regulation of the expression of glucose-regulated protein 75(Grp75), thus suppressing p53-mediated neuronal apoptosis under Aβ-related stresses; and(iii) decreasing toxic soluble Aβ peptides. Overall, our work suggested that vanadyl complexes may have great potential for effective therapeutic treatment of AD.