Alzheimer's Aβ Research Articles

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-β (Aβ) in Alzheimer’s disease and α-synuclein (αS) in Parkinson’s disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of αS, Aβ and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases.

Functional Reciprocity of Amyloids and Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation, and Inflammation.

Pathological self-assembly is a concept that is classically associated with amyloids, such as amyloid-β (Aβ) in Alzheimer's disease and α-synuclein in Parkinson's disease. In prokaryotic organisms, amyloids are assembled extracellularly in a similar fashion to human amyloids. Pathogenicity of amyloids is attributed to their ability to transform into several distinct structural states that reflect their downstream biological consequences. While the oligomeric forms of amyloids are thought to be responsible for their cytotoxicity via membrane permeation, their fibrillar conformations are known to interact with the innate immune system to induce inflammation. Furthermore, both eukaryotic and prokaryotic amyloids can self-assemble into molecular chaperones to bind nucleic acids, enabling amplification of Toll-like receptor (TLR) signaling. Recent work has shown that antimicrobial peptides (AMPs) follow a strikingly similar paradigm. Previously, AMPs were thought of as peptides with the primary function of permeating microbial membranes. Consistent with this, many AMPs are facially amphiphilic and can facilitate membrane remodeling processes such as pore formation and fusion. We show that various AMPs and chemokines can also chaperone and organize immune ligands into amyloid-like ordered supramolecular structures that are geometrically optimized for binding to TLRs, thereby amplifying immune signaling. The ability of amphiphilic AMPs to self-assemble cooperatively into superhelical protofibrils that form structural scaffolds for the ordered presentation of immune ligands like DNA and dsRNA is central to inflammation. It is interesting to explore the notion that the assembly of AMP protofibrils may be analogous to that of amyloid aggregates. Coming full circle, recent work has suggested that Aβ and other amyloids also have AMP-like antimicrobial functions. The emerging perspective is one in which assembly affords a more finely calibrated system of recognition and response: the detection of single immune ligands, immune ligands bound to AMPs, and immune ligands spatially organized to varying degrees by AMPs, result in different immunologic outcomes. In this framework, not all ordered structures generated during multi-stepped AMP (or amyloid) assembly are pathological in origin. Supramolecular structures formed during this process serve as signatures to the innate immune system to orchestrate immune amplification in a proportional, situation-dependent manner.

Intracisternal injection of beta-amyloid seeds promotes cerebral amyloid angiopathy

Beta amyloid (Aβ) is a key component of parenchymal Aβ plaques and vascular Aβ fibrils, which lead to cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD). Recent studies have revealed that Aβ contained in the cerebrospinal fluid (CSF) can re-enter into brain through paravascular spaces. However, whether Aβ in CSF may act as a constant source of pathogenic Aβ in AD is still unclear. This study aimed to examine whether Aβ pathology could be worsened when CSF Aβ level was enhanced by intra-cisternal infusion of aged brain extract containing abundant Aβ in TgCRND8 host mice. TgCRND8 mouse is an AD animal model which develops predominant parenchymal Aβ plaques in the brain at as early as 3 months of age. Here, we showed that single intracisternal injection of Aβ seeds into TgCRND8 mice before the presence of Aβ pathology induced robust prion-like propagation of CAA within 90 days. The induced CAA is mainly distributed in the cerebral cortex, hippocampus and thalamus of TgCRND8 mice. Surprisingly, despite the robust increase in CAA levels, the TgCRND8 mice had a marked decrease in parenchymal Aβ plaques and the plaques related neuroinflammation in the brains compared with the control mice. These results amply indicate that Aβ in CSF may act as a source of Aβ contributing to the growth of vascular Aβ deposits in CAA. Our findings provide experimental evidence to unravel the mechanisms of CAA formation and the potential of targeting CSF Aβ for CAA.

Zinc binding promotes greater hydrophobicity in Alzheimer's Aβ42 peptide than copper binding: Molecular dynamics and solvation thermodynamics studies.

The aggregation of Aβ42 peptides is considered as one of the main causes for the development of Alzheimer's disease. In this context, Zn2+ and Cu2+ play a significant role in regulating the aggregation mechanism, due to changes in the structural and the solvation free energy of Aβ42. In practice, experimental studies are not able to determine the latter properties, since the Aβ42-Zn2+ and Aβ42-Cu2+ peptide complexes are intrinsically disordered, exhibiting rapid conformational changes in the aqueous environment. Here, we investigate atomic structural variations and the solvation thermodynamics of Aβ42, Aβ42-Cu2+ , and Aβ42-Zn2+ systems in explicit solvent (water) by using quantum chemical structures as templates for a metal binding site and combining extensive all-atom molecular dynamics (MD) simulations with a thorough solvation thermodynamic analysis. Our results show that the zinc and copper coordination results in a significant decrease of the solvation free energy in the C-terminal region (Met35-Val40), which in turn leads to a higher structural disorder. In contrast, the β-sheet formation at the same C-terminal region indicates a higher solvation free energy in the case of Aβ42. The solvation free energy of Aβ42 increases upon Zn2+ binding, due to the higher tendency of forming the β-sheet structure at the Leu17-Ala42 residues, in contrast to the case of binding with Cu2+ . Finally, we find the hydrophobicity of Aβ42-Zn2+ in water is greater than in the case of Aβ42-Cu2+ .

Amyloid Metabolism and Amyloid-Targeting Blood-Based Biomarkers of Alzheimer's Disease.

Amyloid-β (Aβ) is a key protein in Alzheimer's disease (AD) in that its accumulation induces complex pathological changes. Although there has been extensive research on the metabolism of Aβ in AD, new compelling results have recently emerged. Historically, the production and clearance of Aβ have been thought to originate in the central nervous system (CNS). However, recent evidence suggests that the production and clearance of Aβ can also occur in the peripheral system, and that the peripherally driven Aβ migrates to the CNS and induces amyloidopathy with subsequent AD pathologic changes in the brain. This concept implies that AD is not restricted to the CNS but is a systemic disease instead. As such, the development of blood-based biomarkers targeting Aβ is of great interest. Central and peripheral Aβ are both active contributors to the pathology of AD and interact bidirectionally. Measuring peripheral Aβ is not just observing the reflection of the residual Aβ removed from the CNS but also tracking the ongoing process of AD pathology. Additionally, blood-based biomarkers could be a more accessible tool in clinical and research settings. Through arduous research, several blood-based biomarker assays have demonstrated notable results. In this review, we describe the metabolism of Aβ and the amyloid-targeting blood-based biomarkers of AD.

A kinetic ensemble of the Alzheimer's Aβ peptide

A kinetic ensemble of the Alzheimer's Aβ peptide

Liquid‐Like Phases Preorder Peptides for Supramolecular Assembly

AbstractControlling supramolecular assembly remains a major challenge for materials science and synthetic biology. Biopolymers organize into multimolecular architectures via two‐step nucleation processes involving dynamic intermediate solute‐rich phases. Here we present spectroscopic analyses of metastable phases formed with a congener of the Alzheimer's disease Aβ peptide that reveals diverse populations of single β‐sheets. The degree of order in this liquid‐like particle phase is remarkable both in the range of sheets and the selection of a single propagating nucleus. The resulting fibril seed is less stable in solution and cooperatively transforms into another fibril. The conformational dynamics of this peptide provide a mechanistic model for controlling the range of polymorphic amyloid assemblies in health and disease.

Is the p3 Peptide (Aβ17-40, Aβ17-42) Relevant to the Pathology of Alzheimer's Disease?1.

Despite the vast heterogeneity of amyloid plaques isolated from the brains of those with Alzheimer's Disease (AD), the basis of the Amyloid Cascade Hypothesis targets a single peptide, the amyloid-β (Aβ) peptide. The countless therapeutic efforts targeting the production and aggregation of this specific peptide have been met with disappointment, leaving many to question the role of Aβ in AD. An alternative cleavage product of the Amyloid-β protein precursor, called the p3 peptide, which has also been isolated from the brains of AD patients, has been largely absent from most Aβ-related studies. Typically referred to as non-amyloidogenic and even suggested as neuroprotective, the p3 peptide has garnered little attention aside from some conflicting findings on cytotoxicity and potential self-assembly to form higher order aggregates. Herein, we report an extensive analysis of the findings surrounding p3 and offer some evidence as to why it may not be as innocuous as previously suggested.

Exposure of CuO Nanoparticles Contributes to Cellular Apoptosis, Redox Stress, and Alzheimer's Aβ Amyloidosis.

Fe2O3, CuO and ZnO nanoparticles (NP) have found various industrial and biomedical applications. However, there are growing concerns among the general public and regulators about their potential environmental and health impacts as their physio-chemical interaction with biological systems and toxic responses of the latter are complex and not well understood. Herein we first reported that human SH-SY5Y and H4 cells and rat PC12 cell lines displayed concentration-dependent neurotoxic responses to insults of CuO nanoparticles (CuONP), but not to Fe2O3 nanoparticles (Fe2O3NP) or ZnO nanoparticles (ZnONP). This study provides evidence that CuONP induces neuronal cell apoptosis, discerns a likely p53-dependent apoptosis pathway and builds out the relationship between nanoparticles and Alzheimer’s disease (AD) through the involvement of reactive oxygen species (ROS) and increased Aβ levels in SH-SY5Y and H4 cells. Our results implicate that exposure to CuONP may be an environmental risk factor for AD. For public health concerns, regulation for environmental or occupational exposure of CuONP are thus warranted given AD has already become a pandemic.

Neurofilament Proteins as Prognostic Biomarkers in Neurological Disorders.

Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are neuron-specific cytoskeletal components. Neurofilaments are axonal structural components and integral components of synapses, which are important for neuronal electric signal transmissions along the axons and post-translational modification. Abnormal assembly of neurofilaments is found in several human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and hereditary sensory-motor neuropathy (HSMN). In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson's disease (PD), Aβ and tau in Alzheimer's disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS). When axon damage occurs in central nervous disorders, neurofilament proteins are released and delivered into cerebrospinal fluid (CSF), which are then circulated into blood. New quantitative analyses and assay techniques are well-developed for the detection of neurofilament proteins, particularly NF-L and the phosphorylated NF-H (pNF-H) in CSF and serum. This review discusses the potential of using peripheral blood NF quantities and evaluating the severity of damage in the nervous system. Intermediate filaments could be promising biomarkers for evaluating disease progression in different nervous system disorders.

Analysis of Cerebrospinal Fluid Soluble TREM2 and Polymorphisms in Sporadic Parkinson's Disease in a Chinese Population.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that mediates the degradation disorder of amyloid β (Aβ) in Alzheimer's disease. However, the role of TREM2 in Parkinson's disease (PD) and α-Synclein (α-Syn) degradation is largely unknown. In this case-control study on Chinese population, we sequenced for polymorphisms in exon 2 of the TREM2 gene in 1,292 individuals, PD cases (n = 612), healthy controls (n = 680) by Sanger sequence, and compared the distribution of allelic frequencies between the two groups by the Fisher's exact test. Additionally, we developed and used the enzyme-linked immunosorbent assay to evaluated soluble TREM2 (sTREM2) levels in the cerebrospinal fluid (CSF), and plasma in partial of sequenced groups (55 PD and 40 healthy controls) analyzed their relationship with total a-syn (t-a-Syn). Two novel variants were detected in exon 2 of the TREM2 gene, namely, p.S81 N, p.G58D; however, these were not significantly associated with PD (612 PD and 680 healthy controls). sTREM2 in CSF was significantly upregulated in PD patients compared to healthy controls (433.1 ± 24.7 pg/mL vs. 275.2 ± 17.9 pg/mL, p < 0.0001), but not in plasma (281.7 ± 29.3 pg/mL vs. 257.8 ± 16.5 pg/mL, p = 0.805). In PD patients, sTREM2 was positively correlated with t-α-syn (r = 0.62, p = 0.0001) in CSF, but not in plasma (r = 0.02, p = 0.89). Although it may not indicate that exon 2 polymorphisms of TREM2 play a role in the pathogenesis of PD in the Chinese population, our findings described above highlight the relevance of CSF sTREM2 as a promising biomarker and are extremely possible to the therapeutic target for PD in the future.

Reduction of AHI1 in the serum of Taiwanese with probable Alzheimer’s disease

ObjectiveThe development of blood-based biomarkers for early diagnosis and treatment of Alzheimer’s disease (AD) is desirable. In AD model mouse brain and neuronal cells, Abelson helper integration site-1 (AHI1) protein is reduced. AHI1 facilitates intracellular amyloid precursor protein (APP) translocation to inhibit amyloidogenic pathology of AD, and thus may be an AD biomarker. MethodsThis study was conducted among 32 AD patients and 54 healthy control (HC) subjects. AHI1-related protein levels from initially collected serum samples in each group were screened using Western blotting. The protein concentrations of AHI1 and amyloid-β (Aβ), peptide(s) derived from APP, from all serum samples were analyzed using ELISA. ResultsIn AD serum, AHI1 and a large truncated C-terminal APP fragment were significantly reduced. The average concentrations of serum AHI1 and Aβ in AD were significantly lower than those in HC. Notably, AHI1 concentration in HC serum was decreased in an age-dependent manner, while it was consistently low in AD serum and had no correlation with Aβ or mini-mental state examination score. The receiver operating characteristic analysis on all subjects demonstrated an area under curve (AUC) value of 0.7 for AHI1 on AD diagnosis, while the AUC increased to 0.82 on the subjects younger than 77 years old, suggesting a good diagnostic performance of serum AHI1 for AD especially at relatively young age. ConclusionAn early event of AHI1 reduction in the body of AD patients was observed. Serum AHI1 may be valuable for early diagnosis of AD.

Extracellular Vesicles: A Possible Link between HIV and Alzheimer's Disease-Like Pathology in HIV Subjects?

The longevity of people with HIV/AIDS has been prolonged with the use of antiretroviral therapy (ART). The age-related complications, especially cognitive deficits, rise as HIV patients live longer. Deposition of beta-amyloid (Aβ), a hallmark of Alzheimer’s disease (AD), has been observed in subjects with HIV-associated neurocognitive disorders (HAND). Various mechanisms such as neuroinflammation induced by HIV proteins (e.g., Tat, gp120, Nef), excitotoxicity, oxidative stress, and the use of ART contribute to the deposition of Aβ, leading to dementia. However, progressive dementia in older subjects with HIV might be due to HAND, AD, or both. Recently, extracellular vesicles (EVs)/exosomes, have gained recognition for their importance in understanding the pathology of both HAND and AD. EVs can serve as a possible link between HIV and AD, due to their ability to package and transport the toxic proteins implicated in both AD and HIV (Aβ/tau and gp120/tat, respectively). Given that Aß is also elevated in neuron-derived exosomes isolated from the plasma of HIV patients, it is reasonable to suggest that neuron-to-neuron exosomal transport of Aβ and tau also contributes to AD-like pathology in HIV-infected subjects. Therefore, exploring exosomal contents is likely to help distinguish HAND from AD. However, future prospective clinical studies need to be conducted to compare the exosomal contents in the plasma of HIV subjects with and without HAND as well as those with and without AD. This would help to find new markers and develop new treatment strategies to treat AD in HIV-positive subjects. This review presents comprehensive literatures on the mechanisms contributing to Aβ deposition in HIV-infected cells, the role of EVs in the propagation of Aβ in AD, the possible role of EVs in HIV-induced AD-like pathology, and finally, possible therapeutic targets or molecules to treat HIV subjects with AD.

Design, synthesis, and biological activity evaluation of BACE1 inhibitors with antioxidant activity.

The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid peptides (Aβ) in Alzheimer's disease (AD), antioxidants could attenuate the AD syndrome and prevent the disease progression. In this study, BACE1 inhibitors (D1-D18) with free radical-scavenging activities were synthesized by molecular hybridization of 2-aminopyridine with natural antioxidants. The biological activity evaluation showed that D1 had obvious inhibitory activity against BACE1, and strong antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS+• ) assay, which could be used as a lead compound for further study.

Reciprocal Predictive Relationships between Amyloid and Tau Biomarkers in Alzheimer's Disease Progression: An Empirical Model.

There is an urgent need to understand the relationships between amyloid-β (Aβ) and tau in the progression of Alzheimer's disease to identify treatment targets. Here we examine reciprocal predictions of brain Aβ burden quantified by positron emission tomography and CSF concentrations of Aβ42 and phosphorylated tau (p-tau). Each biomarker was examined over 48 months in two separate cross-lagged models; one in asymptomatic healthy elderly people (men and women), and one in patients with Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI). The models examine predictions of each biomarker on the progression of the others, considering each previous and concurrent measure. In healthy elderly, lower CSF Aβ42 predicted Aβ deposition and reciprocally, Aβ burden predicted a decrease in CSF Aβ42. Lower CSF Aβ42 predicted an increase in CSF p-tau, and CSF p-tau predicted Aβ deposition. In AD/MCI, lower CSF Aβ42 predicted Aβ deposition and Aβ burden reciprocally predicted CSF Aβ42 changes; however, in contrast to healthy elderly, CSF p-tau concentrations did not predict Aβ biomarkers, or vice versa. In post hoc models examining cognitive status, CSF Aβ42 predicted Mini Mental State Examination (MMSE) scores in healthy elderly, whereas Aβ burden and CSF p-tau predicted MMSE scores in AD/MCI. The findings describe reciprocal predictions between Aβ and tau biomarkers in healthy elderly and they implicate mechanisms underlying low CSF Aβ42 in Alzheimer's disease pathogenesis and progression. In symptomatic Alzheimer's disease, CSF Aβ42 and Aβ deposition predicted each other; however, Aβ and CSF p-tau progressed independently and they independently predicted cognitive decline.SIGNIFICANCE STATEMENT This study offers empirical evidence concerning the hypothesized "amyloid cascade", as it progressed over 4 years in healthy elderly people and in Alzheimer's disease patients. In healthy elderly, CSF amyloid changes predicted amyloid deposition, CSF phosphorylated tau concentrations, and a decline in cognitive status. Phosphorylated tau concentrations specifically predicted amyloid deposition. In Alzheimer's disease patients, although amyloid deposition and CSF amyloid changes continued to "cascade", there was no evidence to suggest that amyloid and tau biomarkers predicted each other, although both amyloid deposition and CSF tau progression predicted cognitive decline independently. Taking advantage of repeated amyloid PET and CSF measures, this dynamic view offers new insight into the progression of Alzheimer's disease biomarkers and their relationships with cognitive decline.

Aging, Metabolism, Synaptic Activity, and Aβ in Alzheimer's Disease.

Aging, Metabolism, Synaptic Activity, and Aβ in Alzheimer's Disease.

Oroxylum indicum (L.) extract protects human neuroblastoma SH‑SY5Y cells against β‑amyloid‑induced cell injury.

It has been reported that amyloid β peptide, the major component of senile plaques, serves a critical role in the development and progression of Alzheimer's disease (AD) by generating reactive oxygen species (ROS), leading to oxidative stress. The aim of the present study was to investigate the protective effect of Oroxylum indicum (L.) extract against Aβ25‑35‑induced oxidative stress and cell injury using SH‑SY5Y cells as a model, and at exploring the underlying mechanisms. The results revealed that the exposure of cells to 20µM Aβ25‑35 significantly increased cellular oxidative stress, as evidenced by the increased ROS levels. Aβ25‑35 treatment also increased caspase‑3/7 activity and lactate dehydrogenase (LDH) release, and caused viability loss. Oroxylumindicum treatment not only attenuated the generation of ROS and suppressed caspase‑3/7 activity but also reduced the neurotoxicity of Aβ25‑35 in a concentration‑dependent manner, as evidenced by the increased cell viability and decreased LDH release. Treatment with Oroxylumindicum also increased superoxide dismutase (SOD) and catalase (CAT) activity, increased the phosphorylation of Akt and cAMP‑responsive element binding protein (CREB), and contributed to the upregulation of Bcl‑2 protein. In combination, these results indicated that Oroxylumindicum extract could protect SH‑SY5Y cells against Aβ25‑35‑induced cell injury, at least partly, by inhibiting oxidative stress, increasing SOD and CAT activity, attenuating caspase 3/7 activity and promoting the cell survival pathway, Akt/CREB/Bcl‑2. The approach used in the present study may also be useful for preventing the neurotoxicity induced by Aβ in AD and related neurodegenerative diseases. Further studies investigating the activity of Oroxylumindicum extract invivo are now required.

Neuroprotective Potential of Curcumin-Loaded Nanostructured Lipid Carrier in an Animal Model of Alzheimer's Disease: Behavioral and Biochemical Evidence.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is caused by accumulation of amyloid-β (Aβ) peptide and is associated with neurological abnormalities in learning and memory. The protective role of curcumin on nerve cells, along with a potent antioxidant and free radical scavenging activity, has been widely studied. However, its low bioavailability and limited transport ability across the blood-brain barrier are two major drawbacks of its application in the treatment of different neurodegenerative diseases. The present study was designed to improve the effectiveness of curcumin in the treatment of Aβ-induced cognitive deficiencies in a rat model of AD by loading it into nanostructured lipid carriers (NLCs). The accumulation rate of curcumin (505.76±38.4 ng/g-1 h) in rat brain, as well as its serum levels, were significantly increased by using curcumin-loaded NLCs. The effective role of NLCs for brain delivery of curcumin was confirmed by reduced oxidative stress parameters (ROS formation, lipid peroxidation, and ADP/ATP ratio) in the hippocampal tissue and improvement of spatial memory. Also, histopathological studies revealed the potential of Cur-NLCs in decreasing the hallmarks of Aβ in AD in the animal model. The result of studying the neuroprotective potential of Cur-NLC in both pre-treatment and treatment modes showed that loading curcumin in NLCs is an effective strategy for increasing curcumin delivery to the brain and reducing Aβ-induced neurological abnormalities and memory defects and that it can be the basis for further studies in the area of AD prevention and treatment.

NMR Characterization of Conformational Dynamics and Molecular Assemblies of Proteins.

Dynamic conformational transitions and molecular assemblies are essential properties of proteins, and relevant to their biological and pathological functions. Neurodegenerative diseases are known to be caused by abnormal, toxic assemblies of related proteins, e.g., amyloid β (Aβ) in Alzheimer's disease. Growing evidence indicates that the aggregation of various amyloidogenic proteins, including Aβ, can be highly enhanced at glycolipid membranes, suggesting that dynamic glycolipid-dependent conformational changes of proteins constitute crucial steps for their subsequent pathogenic amyloid fibril formation. It has also been proposed that several proteins, including molecular chaperones, can capture amyloidogenic proteins and thereby suppress their fibrillization. NMR spectroscopy provides a powerful tool for characterizing the conformational dynamics and intermolecular interactions of proteins, as well as for exploring transiently formed weak interactions among proteins in solution with various biomolecules, such as glycolipids. Our research group therefore attempted to elucidate the structural basis of protein-glycolipid and protein-protein interactions that either promote or suppress molecular assemblies of amyloidogenic proteins, using both solution and solid-state NMR methods in conjunction with other biophysical techniques. Our findings provide structural views of molecular processes involving amyloidogenic proteins of clinical and pathological interest and offer clues for the development of drugs to prevent and treat neurodegenerative diseases.

Aβ and tau prion-like activities decline with longevity in the Alzheimer's disease human brain.

The hallmarks of Alzheimer's disease (AD) are the accumulation of Aβ plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of Aβ in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological Aβ conformers. Individuals over 80 years of age had the lowest amounts of prion-like Aβ and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD.