An N-terminal acidic ß-sheet domain is responsible for the metal-accumulation properties of amyloid-ß protofibrils: a molecular dynamics study.

The influence of metal ions on the structure of amyloid- ß (Aß) protofibril models was studied through molecular dynamics to explore the molecular mechanisms underlying metal-induced Aß aggregation relevant in Alzheimer's disease (AD). The models included 36-, 48-, and 188-mers of the Aß42 sequence and two disease-modifying variants. Primary structural effects were observed at the N-terminal domain, as it became susceptible to the presence of cations. Specially when ß-sheets predominate, this motif orients N-terminal acidic residues toward one single face of the ß-sheet, resulting in the formation of an acidic region that attracts cations from the media and promotes the folding of the N-terminal region, with implications in amyloid aggregation. The molecular phenotype of the protofibril models based on Aß variants shows that the AD-causative D7N mutation promotes the formation of N-terminal ß-sheets and accumulates more Zn2+, in contrast to the non-amyloidogenic rodent sequence that hinders the ß-sheets and is more selective for Na+ over Zn2+ cations. It is proposed that forming an acidic ß-sheet domain and accumulating cations is a plausible molecular mechanism connecting the elevated affinity and concentration of metals in Aß fibrils to their high content of ß-sheet structure at the N-terminal sequence.

Molecular Mechanisms Linking Osteoarthritis and Alzheimer's Disease: Shared Pathways, Mechanisms and Breakthrough Prospects.

Alzheimer's disease (AD) is a progressive neurodegenerative disease mostly affecting the elderly population. It is characterized by cognitive decline that occurs due to impaired neurotransmission and neuronal death. Even though deposition of amyloid beta (Aß) peptides and aggregation of hyperphosphorylated TAU have been established as major pathological hallmarks of the disease, other factors such as the interaction of genetic and environmental factors are believed to contribute to the development and progression of AD. In general, patients initially present mild forgetfulness and difficulty in forming new memories. As it progresses, there are significant impairments in problem solving, social interaction, speech and overall cognitive function of the affected individual. Osteoarthritis (OA) is the most recurrent form of arthritis and widely acknowledged as a whole-joint disease, distinguished by progressive degeneration and erosion of joint cartilage accompanying synovitis and subchondral bone changes that can prompt peripheral inflammatory responses. Also predominantly affecting the elderly, OA frequently embroils weight-bearing joints such as the knees, spine and hips leading to pains, stiffness and diminished joint mobility, which in turn significantly impacts the patient's standard of life. Both infirmities can co-occur in older adults as a result of independent factors, as multiple health conditions are common in old age. Additionally, risk factors such as genetics, lifestyle changes, age and chronic inflammation may contribute to both conditions in some individuals. Besides localized peripheral low-grade inflammation, it is notable that low-grade systemic inflammation prompted by OA can play a role in AD pathogenesis. Studies have explored relationships between systemic inflammatory-associated diseases like obesity, hypertension, dyslipidemia, diabetes mellitus and AD. Given that AD is the most common form of dementia and shares similar risk factors with OA-both being age-related and low-grade inflammatory-associated diseases, OA may indeed serve as a risk factor for AD. This work aims to review literature on molecular mechanisms linking OA and AD pathologies, and explore potential connections between these conditions alongside future prospects and innovative treatments.

Alzheimer's Disease: An Updated Overview of Its Genetics.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. It is classified as familial and sporadic. The dominant familial or autosomal presentation represents 1-5% of the total number of cases. It is categorized as early onset (EOAD; <65 years of age) and presents genetic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or the Amyloid precursor protein (APP). Sporadic AD represents 95% of the cases and is categorized as late-onset (LOAD), occurring in patients older than 65 years of age. Several risk factors have been identified in sporadic AD; aging is the main one. Nonetheless, multiple genes have been associated with the different neuropathological events involved in LOAD, such as the pathological processing of Amyloid beta (Aß) peptide and Tau protein, as well as synaptic and mitochondrial dysfunctions, neurovascular alterations, oxidative stress, and neuroinflammation, among others. Interestingly, using genome-wide association study (GWAS) technology, many polymorphisms associated with LOAD have been identified. This review aims to analyze the new genetic findings that are closely related to the pathophysiology of AD. Likewise, it analyzes the multiple mutations identified to date through GWAS that are associated with a high or low risk of developing this neurodegeneration. Understanding genetic variability will allow for the identification of early biomarkers and opportune therapeutic targets for AD.

Grape juice reduces the effects of amyloid ß aggregation phenotype and extends the longevity in Caenorhabditis elegans.

OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of aggregated amyloid-ß (Aß) peptides. Several natural compounds have been proposed against this disease and grape products are among these. However, little is known about grape juice potential. Transgenic Caenorhabditis elegans (C. elegans) strains that express human Aß have been used as an in vivo model for AD. METHODS: In this study, we have exposed CL2006 worms to nine different juices obtained from different cultivars. RESULTS: Cora, Bordo, Isabel, Isabel Precoce, BRS-Magna, BRS-Rubea and BRS-Violeta juices improved the behavioral phenotype (paralysis) that is caused by Aß aggregation in the transgenic animals at the concentrations tested and no toxic effects were found. Some juices were also able to increase the worm's lifespan. We could not attribute lifespan increase and paralysis reduction with any specific compound found in the phytochemical analysis. DISCUSSION: Our data indicate that the rich constitution of the juices is responsible for attenuating the phenotype caused by Aß aggregation in C. elegans.

Clathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments.

One of the hallmarks of Alzheimer's disease is the accumulation of toxic amyloid-ß (Aß) peptides in extracellular plaques. The direct precursor of Aß is the carboxyl-terminal fragment ß (or C99) of the amyloid precursor protein (APP). C99 is detected at elevated levels in Alzheimer's disease brains, and its intracellular accumulation has been linked to early neurotoxicity independently of Aß. Despite this, the causes of increased C99 levels are poorly understood. Here, we demonstrate that APP interacts with the clathrin vesicle adaptor AP-1 (adaptor protein 1), and we map the interaction sites on both proteins. Using quantitative kinetic trafficking assays, established cell lines and primary neurons, we also show that this interaction is required for the transport of APP from the trans-Golgi network to endosomes. In addition, disrupting AP-1-mediated transport of APP alters APP processing and degradation, ultimately leading to increased C99 production and Aß release. Our results indicate that AP-1 regulates the subcellular distribution of APP, altering its processing into neurotoxic fragments.

Examining the Ensembles of Amyloid-ß Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method.

The amyloid-ß (Aß) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aß-40 and Aß-42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer's disease (AD). Experiments have shown that even though the natural abundance of Aß-42 is smaller than that for Aß-40, the Aß-42 is more aggregation-prone compared to Aß-40. Moreover, several single-point mutations are associated with early onset forms of AD. This work analyzes coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations of normal Aß-40 and Aß-42 monomers, along with six single-point mutations associated with early onset disease. We analyzed the simulations using the energy landscape visualization method (ELViM), a reaction-coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins.

Ilex paraguariensis extract provides increased resistance against oxidative stress and protection against Amyloid beta-induced toxicity compared to caffeine in Caenorhabditis elegans.

Ilex paraguariensis is a plant from South America, used to prepare a tea-like beverage rich in caffeine and polyphenols with antioxidant proprieties. Caffeine consumption is associated with a lower risk of age-associated neuropathologies, besides several extracts that have antioxidant proprieties are known to be neuroprotective, and oxidative stress strongly correlates with Aß-toxicity. This study aims to investigate the neuroprotective effects of the Ilex paraguariensis hydroalcoholic extract (IPHE) and to evaluate if caffeine agent present in IPHE exerts neuroprotective effects in an amyloid beta-peptide (Aß)-induced toxicity in Caenorhabditis elegans. The wild-type and CL2006 worms were treated with IPHE (2 and 4 mg/mL) or caffeine (200 and 400 µM) since larval stage 1 (L1) until they achieved the required age for each assay. IPHE and caffeine increased the lifespan and appeared to act directly by reactive oxygen species (ROS) scavenger in both wild-type and CL2006 worms, also conferred resistance against oxidative stress in wild-type animals. Furthermore, both treatments delayed Aß-induced paralysis and decreased AChE activity in CL2006. The protective effect of IPHE against Aß-induced paralysis was found to be dependent on heat shock factor hsf-1 and FOXO-family transcription factor daf-16, which are respectively involved in aging-related processes and chaperone synthesis, while that of caffeine was dependent only on daf-16. Mechanistically, IPHE and caffeine decreased the levels of Aß mRNA in the CL2006 worms; however, only IPHE induced expression of the heat shock chaperonin hsp-16.2, involved in protein homeostasis. The results were overall better when treated with IPHE than with caffeine.

Association of Vitamin D Receptor Polymorphisms with Amyloid-ß Transporters Expression and Risk of Mild Cognitive Impairment in a Chilean Cohort.

BACKGROUND: Amyloid-ß peptide (Aß) deposition in Alzheimer's disease (AD) is due to an imbalance in its production/clearance rate. Aß is transported across the blood-brain barrier by LRP1 and P-gp as efflux transporters and RAGE as influx transporter. Vitamin D deficit and polymorphisms of the vitamin D receptor (VDR) gene are associated with high prevalence of mild cognitive impairment (MCI) and AD. Further, vitamin D promotes the expression of LRP1 and P-gp in AD-animal model brains. OBJECTIVE: To associate VDR polymorphisms Apa I (rs7975232), Taq I (rs731236), and Fok I (rs2228570) with the risk of developing MCI in a Chilean population, and to evaluate the relationship of these polymorphisms to the expression of VDR and Aß-transporters in peripheral blood mononuclear cells (PBMCs). METHODS: VDR polymorphisms Apa I, Taq I, and Fok I were determined in 128 healthy controls (HC) and 66 MCI patients. mRNA levels of VDR and Aß-transporters were evaluated in subgroups by qPCR. RESULTS: Alleles A of Apa I and C of Taq I were associated with a lower risk of MCI. HC with the Apa I AA genotype had higher mRNA levels of P-gp and LRP1, while the expression of VDR and RAGE were higher in MCI patients and HC. For Fok I, the TC genotype was associated with lower expression levels of Aß-transporters in both groups. CONCLUSION: We propose that the response to vitamin D treatment will depend on VDR polymorphisms, being more efficient in carriers of protective alleles of Apa I polymorphism.

The Prion-like Properties of Amyloid-beta Peptide and Tau: Is there Any Risk of Transmitting Alzheimer's Disease During Neurosurgical Interventions?

Recent studies have recognized similarities between the peptides involved in the neuropathology of Alzheimer's disease and prions. The Tau protein and the Amyloid ß peptide represent the theoretical pillars of Alzheimer's disease development. It is probable that there is a shared mechanism for the transmission of these substances and the prion diseases development; this presumption is based on the presentation of several cases of individuals without risk factors who developed dementia decades after a neurosurgical procedure. This article aims to present the role of Aß and Tau, which underlie the pathophysiologic mechanisms involved in the AD and their similarities with the prion diseases infective mechanisms by means of the presentation of the available evidence at molecular (in-vitro), animal, and human levels that support the controversy on whether these diseases might be transmitted in neurosurgical interventions, which may constitute a wide public health issue.

Age-Dependent Decline in Synaptic Mitochondrial Function Is Exacerbated in Vulnerable Brain Regions of Female 3xTg-AD Mice.

Synaptic aging has been associated with neuronal circuit dysfunction and cognitive decline. Reduced mitochondrial function may be an early event that compromises synaptic integrity and neurotransmission in vulnerable brain regions during physiological and pathological aging. Thus, we aimed to measure mitochondrial function in synapses from three brain regions at two different ages in the 3xTg-AD mouse model and in wild mice. We found that aging is the main factor associated with the decline in synaptic mitochondrial function, particularly in synapses isolated from the cerebellum. Accumulation of toxic compounds, such as tau and Aß, that occurred in the 3xTg-AD mouse model seemed to participate in the worsening of this decline in the hippocampus. The changes in synaptic bioenergetics were also associated with increased activation of the mitochondrial fission protein Drp1. These results suggest the presence of altered mechanisms of synaptic mitochondrial dynamics and their quality control during aging and in the 3xTg-AD mouse model; they also point to bioenergetic restoration as a useful therapeutic strategy to preserve synaptic function during aging and at the early stages of Alzheimer's disease (AD).

Modulation of MicroRNAs as a Potential Molecular Mechanism Involved in the Beneficial Actions of Physical Exercise in Alzheimer Disease.

Alzheimer disease (AD) is one of the most common neurodegenerative diseases, affecting middle-aged and elderly individuals worldwide. AD pathophysiology involves the accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain, along with chronic neuroinflammation and neurodegeneration. Physical exercise (PE) is a beneficial non-pharmacological strategy and has been described as an ally to combat cognitive decline in individuals with AD. However, the molecular mechanisms that govern the beneficial adaptations induced by PE in AD are not fully elucidated. MicroRNAs are small non-coding RNAs involved in the post-transcriptional regulation of gene expression, inhibiting or degrading their target mRNAs. MicroRNAs are involved in physiological processes that govern normal brain function and deregulated microRNA profiles are associated with the development and progression of AD. It is also known that PE changes microRNA expression profile in the circulation and in target tissues and organs. Thus, this review aimed to identify the role of deregulated microRNAs in the pathophysiology of AD and explore the possible role of the modulation of microRNAs as a molecular mechanism involved in the beneficial actions of PE in AD.

Novel monoclonal antibody 3B8 specifically recognizes pyroglutamate-modified amyloid ß 3-42 peptide in brain of AD patients and 3xTg-AD transgenic mice.

In addition to the full-length beta-amyloid peptides (Aß 1-40/42), several Aß variants, truncated at their N- or C-termini and bearing different post-translational modifications, have been detected in the brain of Alzheimer´s disease (AD) patients. AßN3(pE), an Aß peptide bearing an amino-terminal pyroglutamate at position 3, is a significant constituent of intracellular, extracellular and vascular Aß deposits in brain tissue from individuals with AD and Down syndrome. Pioneering immunotherapy studies have primarily focused on the full-length Aß peptide, disregarding the presence of N-truncated/modified species. However, in recent years, increasing attention has been directed towards AßN3(pE), in both pre-clinical studies and clinical trials. In the present study, we generated and characterized an anti-AßN3(pE) mouse monoclonal antibody (3B8) that recognizes amyloid aggregates in brain tissue from AD patients and in 3xTg-AD transgenic mice. To identify the epitope recognized by 3B8, a library of random heptapeptides fused to the minor coat protein of M13 phage was screened. Results from screening, along with those from ELISA assays against distinct Aß fragments, suggest recognition of two conformational epitopes present in AßN3(pE) and Aß 3-42, regardless of the glutamate-pyroglutamate modification. The novel 3B8 antibody may be useful in future therapeutic and diagnostic applications for AD.

Bacillus Subtilis Delays Neurodegeneration and Behavioral Impairment in the Alzheimer's Disease Model Caenorhabditis Elegans.

Multiple causes, apart from genetic inheritance, predispose to the production and aggregation of amyloid-ß (Aß) peptide and Alzheimer's disease (AD) development in the older population. There is currently no therapy or medicine to prevent or delay AD progression. One novel strategy against AD might involve the use of psychobiotics, probiotic gut bacteria with specific mental health benefits. Here, we report the neuronal and behavioral protective effects of the probiotic bacterium Bacillus subtilis in a Caenorhabditis elegans AD model. Aging and neuronal deterioration constitute important risk factors for AD development, and we showed that B. subtilis significantly delayed both detrimental processes in the wild-type C. elegans strain N2 compared with N2 worms colonized by the non-probiotic Escherichia coli OP50 strain. Importantly, B. subtilis alleviated the AD-related paralysis phenotype of the transgenic C. elegans strains CL2120 and GMC101 that express, in body wall muscle cells, the toxic peptides Aß3-42 and Aß1-42, respectively. B. subtilis-colonized CL2355 worms were protected from the behavioral deficits (e.g., poor chemotactic response and decreased body bends) produced by pan-neuronal Aß1-42 expression. Notably, B. subtilis restored the lifespan level of C. elegans strains that express Aß to values similar to the life expectancy of the wild-type strain N2 fed on E. coli OP50 cells. The B. subtilis proficiencies in quorum-sensing peptide (i.e., the Competence Sporulation Factor, CSF) synthesis and gut-associated biofilm formation (related to the anti-aging effect of the probiotic) play a crucial role in the anti-AD effects of B. subtilis. These novel results are discussed in the context of how B. subtilis might exert its beneficial effects from the gut to the brain of people with or at risk of developing AD.

Assessing the therapeutic potential of Graptopetalum paraguayense on Alzheimer's disease using patient iPSC-derived neurons.

Alzheimer's disease (AD) is the most common type of dementia and also one of the leading causes of death worldwide. However, the underlying mechanisms remain unclear, and currently there is no drug treatment that can prevent or cure AD. Here, we have applied the advantages of using induced pluripotent stem cell (iPSC)-derived neurons (iNs) from AD patients, which are able to offer human-specific drug responsiveness, in order to evaluate therapeutic candidates for AD. Using approach involving an inducible neurogenin-2 transgene, we have established a robust and reproducible protocol for differentiating human iPSCs into glutamatergic neurons. The AD-iN cultures that result have mature phenotypic and physiological properties, together with AD-like biochemical features that include extracellular ß-amyloid (Aß) accumulation and Tau protein phosphorylation. By screening using a gene set enrichment analysis (GSEA) approach, Graptopetalum paraguayense (GP) has been identified as a potential therapeutic agent for AD from among a range of Chinese herbal medicines. We found that administration of a GP extract caused a significantly reduction in the AD-associated phenotypes of the iNs, including decreased levels of extracellular Aß40 and Aß42, as well as reduced Tau protein phosphorylation at positions Ser214 and Ser396. Additionally, the effect of GP was more prominent in AD-iNs compared to non-diseased controls. These findings provide valuable information that suggests moving extracts of GP toward drug development, either for treating AD or as a health supplement to prevent AD. Furthermore, our human iN-based platform promises to be a useful strategy when it is used for AD drug discovery.

Amyloid beta oligomers: how pH influences over trimer and pentamer structures?

The aggregation of proteins in the brain is one of the main features of neurodegenerative diseases. In Alzheimer's disease, the abnormal aggregation of Aß-42 is due to intrinsic and extrinsic factors. The latter is due to variations in the environment, such as temperature, salt concentration, and pH. We evaluated the effect of protonation/deprotonation of residues that are part of trimeric and pentameric oligomers at pH 5, pH 6, and pH 7. Molecular dynamics simulation at 200 ns in the canonical ensemble was implemented. The results have revealed that histidine, glutamic acid, and aspartic acid residues showed a protonation/deprotonation effect in oligomers. The root mean square deviation analysis was used to analyze the structural stability at different pHs. We found an increase in hydrophobicity in the side chains of the trimer, while in the pentamer, the structural instability of a compact structure at pH 5 caused the hydrophobic core to open, revealing the hydrophobic region to the environment. At this point, we believe that conformational changes mediated by pH are essential in the aggregation of Aß-42 oligomers.

Preventive Effect of Quercetin in a Triple Transgenic Alzheimer's Disease Mice Model.

Alzheimer's disease (AD) is the most common type of dementia and is the leading cause of disability in elderly people worldwide. Current pharmacological therapies do not cure the disease, and for this reason, some pharmacotherapy studies have investigated preventive treatments focused on modifiable nutritional factors such as diet. Quercetin (Qc) is a flavonoid found in fruits and vegetables that has several biological properties. In this study, we evaluated the effect of chronic oral quercetin administration (100 mg/kg) on neurodegeneration markers and cognitive and emotional deficits in a triple transgenic Alzheimer's disease (3xTg-AD) mouse model using histological and behavioral analyses. Our results suggest that long-term (12 months) oral preventive treatment with quercetin has significant effects on ß-amyloidosis reduction and tends to decrease tauopathy in the hippocampus and amygdala. These decreases positively affected the cognitive functional recovery (without modifying the emotional skills) of 3xTg-AD mice. These findings suggest that preventive and chronic administration of Qc might help to delay the development of histopathological hallmarks and cognitive function deficits in AD.

Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies.

Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when aberrantly folded, can be the cause of some diseases such as Alzheimer's, Parkinson's, and prionic, among others. In these diseases, there are modifications in parts of the protein or in its entirety. A common conformational variation of these IDPs is misfolding and aggregation, forming, for instance, neurotoxic amyloid plaques. In this review, we discuss some IDPs that are involved in neurodegenerative diseases (such as beta amyloid, alpha synuclein, tau, and the "IDP-like" PrP), cancer (p53, c-Myc), and diabetes (amylin), focusing on the structural changes of these IDPs that are linked to such pathologies. We also present the IDP modulation mechanisms that can be explored in new strategies for drug design. Lastly, we show some candidate drugs that can be used in the future for the treatment of diseases caused by misfolded IDPs, considering that cancer therapy has more advanced research in comparison to other diseases, while also discussing recent and future developments in this area of research. Therefore, we aim to provide support to the study of IDPs and their modulation mechanisms as promising approaches to combat such severe diseases.

Amyloid-ß oligomers synaptotoxicity: The emerging role of EphA4/c-Abl signaling in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive memory loss and dementia. The strong correlation between cognitive decline and the loss of synapses supports the idea that synaptic damage is a relevant pathogenic mechanism underlying AD progression. It has been shown that amyloid beta oligomers (AßOs) induce synaptotoxicity ultimately leading to the reduction of dendritic spine density, which underlies cognitive damage. However, the signaling pathways connecting AßOs to synaptic dysfunction have not been completely elucidated. In this review, we have gathered evidence on AßOs receptors and the signaling pathways involved in synaptic damage. We make special emphasis on a new AßOs induced axis that involves the tyrosine kinase ephrin receptor A4 (EphA4) and c-Abl tyrosine kinase activation. EphA4 is a key player in homeostatic plasticity, mediating dendritic spine remodeling and retraction. AßOs aberrantly activate EphA4 leading to dendritic spine elimination. c-Abl is activated in AßOs exposed neurons and in AD patient's brain, and the inhibition of activated c-Abl ameliorates cognitive deficits in AD mouse model. The EphA4 receptor activates c-Abl intracellular signaling. Therefore EphA4 is an emerging AßOs receptor and the activation of the EphA4/c-Abl axis would explain the synaptic spine alterations found in AD.

Plant-based chimeric HPV-virus-like particles bearing amyloid-ß epitopes elicit antibodies able to recognize amyloid plaques in APP-tg mouse and Alzheimer's disease brains.

The main amyloid-beta (Aß) variants detected in the human brain are full-length Aß1-40 and Aß1-42 peptides; however, a significant proportion of AD brain Aß consists also of N-terminal truncated/modified species. The majority of the previous immunotherapeutic strategies targeted the N-terminal immunodominant epitope of the full-length Aß; however, most of the pathological N-truncated forms of Aß lack this critical B cell epitope. Recently, virus-like particles (VLPs), self-assembled structures with highly ordered repetitive patterns on their surface and capable of inducing robust immune responses, were applied as a promising platform for various antigen expressions. In this study, we expressed in plants two chimeric HPV16 L1 capsid proteins obtained by introduction of the ß-amyloid 11-28 epitope (Aß 11-28) into the h4 helix or into the coil regions of the L1 protein. The Aß 11-28 epitope was chosen because it is present in the full-length Aß 1-42 as well as in the truncated/modified amyloid peptide species. After expression, we assembled the chimerical L1/Aß 11-28 into a VLP in which the Aß 11-28 epitope is exposed at very high density (360 times) on the surface of the VLP. The chimeric VLPs elicited in mice Aß-specific antibodies binding to ß-amyloid plaques in APP-tg mouse and AD brains. Our study is the first to demonstrate a successful production in plants and immunogenic properties in mice of chimeric HPV16 L1 VLPs bearing Aß epitope that may be of potential relevance for the development of multivalent vaccines for a multifactorial disease such as AD.

Is cerebral microbleed prevalence relevant as a biomarker in amnestic mild cognitive impairment and mild Alzheimer's disease?

Introduction The search for a reliable neuroimaging biomarker in Alzheimer's disease is a matter of intense research. The presence of cerebral microbleeds seems to be a potential biomarker. However, it is not clear if the presence of microbleeds has clinical usefulness to differentiate mild Alzheimer's disease and amnestic mild cognitive impairment from normal aging. We aimed to verify if microbleed prevalence differs among three groups: mild Alzheimer's disease, amnestic mild cognitive impairment due to Alzheimer's disease, and normal controls. Moreover, we studied whether microbleeds were associated with apolipoprotein E allele ɛ4 status, cerebrospinal fluid amyloid-beta, total and phosphorylated tau protein levels, vascular factors, and cognition. Methods Twenty-eight mild Alzheimer's disease patients, 34 with amnestic mild cognitive impairment and 36 cognitively normal elderly subjects underwent: magnetic resonance imaging with a susceptibility-weighted imaging sequence on a 3T scanner, apolipoprotein E genotyping and a full neuropsychological evaluation. Only amnestic mild cognitive impairment and mild Alzheimer's disease underwent cerebrospinal fluid analysis. We compared the groups and verified if microbleeds were predicted by all other variables. Results Mild Alzheimer's disease presented a higher prevalence of apolipoprotein E allele ɛ4 in relation to amnestic mild cognitive impairment and control group. No significant differences were found between groups when considering microbleed presence. Logistic regression tests failed to find any relationship between microbleeds and the variables. We performed three different regression models using different independent variables: Model 1 - amyloid-beta, phosphorylated tau protein, total tau, apolipoprotein E allele ɛ4 status, age, and sex; Model 2 - vascular risk factors, age, and sex; Model 3 - cognitive scores sex, age, and education. Conclusion Although microbleeds might be related to the Alzheimer's disease process, their presence is not a good candidate for a neuroimaging biomarker of the disease, especially in its early phases.