Structure-based inhibitors of amyloid beta core suggest a common interface with tau.

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline

Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity.

hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP

Cross Amyloid interfaces of Amyloid Beta

The pathological aggregation of proteins into amyloid fibrils is the hallmark for a variety of diseases. The fibrils are morphologically similar- long unbranched filaments displaying a characteristic cross-β structure- despite sometimes large sequence differences, and distinct pathological symptoms. While each amyloid disease is commonly linked to a main misfolded protein, progression of some amyloid diseases affects progression of others. In Alzheimer’s disease (AD), accumulation of amyloid (Aβ) in the brain is thought to occur at the earliest stages of the disease and drive pathogenesis. However, formation of neurofibrillary tangles containing another amyloid protein, tau, correlates much better with cognitive loss. Patients with AD also carry a significant risk for developing type-II diabetes, in which fibrils of human islet amyloid polypeptide (hIAPP) deposit in the kidneys.The common amyloid aggregation motif has posed the hypothesis that one amyloid protein could directly nucleate another via cross-amyloid interactions. To elucidate the molecular basis for these interactions, we used a pioneer method, microcrystal electron diffraction, to determine atomic structures of potential cross-seeding regions of Aβ. We found that fibrils of structurally similar 11-residue segments from hIAPP and Aβ induce amyloid formation of both parent proteins through self- and cross-seeding. Structure-based inhibitors designed for the hIAPP segment were able to reduce cytotoxicity of both proteins. Additionally, we designed inhibitors for second potential cross-seeding region of Aβ. While reducing Aβ aggregation and toxicity as designed, the inhibitor also reduces Aβ-mediated tau aggregation, and moreover reduces aggregation and self-seeding of tau fibrils. Using mutagenesis and structural alignment, we find that tau and Aβ may contain similar interfaces. Fully understanding cross-amyloid interfaces could provide insight into disease progression and potentially also lead to therapeutic targets

Cross Amyloid interfaces of Amyloid Beta

The pathological aggregation of proteins into amyloid fibrils is the hallmark for a variety of diseases. The fibrils are morphologically similar- long unbranched filaments displaying a characteristic cross-β structure- despite sometimes large sequence differences, and distinct pathological symptoms. While each amyloid disease is commonly linked to a main misfolded protein, progression of some amyloid diseases affects progression of others. In Alzheimer’s disease (AD), accumulation of amyloid (Aβ) in the brain is thought to occur at the earliest stages of the disease and drive pathogenesis. However, formation of neurofibrillary tangles containing another amyloid protein, tau, correlates much better with cognitive loss. Patients with AD also carry a significant risk for developing type-II diabetes, in which fibrils of human islet amyloid polypeptide (hIAPP) deposit in the kidneys.The common amyloid aggregation motif has posed the hypothesis that one amyloid protein could directly nucleate another via cross-amyloid interactions. To elucidate the molecular basis for these interactions, we used a pioneer method, microcrystal electron diffraction, to determine atomic structures of potential cross-seeding regions of Aβ. We found that fibrils of structurally similar 11-residue segments from hIAPP and Aβ induce amyloid formation of both parent proteins through self- and cross-seeding. Structure-based inhibitors designed for the hIAPP segment were able to reduce cytotoxicity of both proteins. Additionally, we designed inhibitors for second potential cross-seeding region of Aβ. While reducing Aβ aggregation and toxicity as designed, the inhibitor also reduces Aβ-mediated tau aggregation, and moreover reduces aggregation and self-seeding of tau fibrils. Using mutagenesis and structural alignment, we find that tau and Aβ may contain similar interfaces. Fully understanding cross-amyloid interfaces could provide insight into disease progression and potentially also lead to therapeutic targets

The Role of Caregivers in Physical Activity for Older Adults With Alzheimer's Disease

This study examined the determinants of physical activity (PA) for older adults with Alzheimer's disease (AD) to learn more about how to promote PA in this population. Caregivers of older adults with AD (N = 99) provided information related to care recipient's PA, as well as addressed sociodemographics and perceptions about their care recipient's PA. Gender of care recipient was a significant predictor of PA (β = .80, P < .05); men with AD participated in more PA than women with AD. Also, caregiver's outcome expectation for care recipient's PA also predicted more PA (β = .82, P < .05). Caregiver's perceived benefits of PA (outcome expectation) for their care recipient partially mediated the relationship between self-efficacy for care recipient's PA and the reported levels of PA for the care recipient. This study demonstrated the importance of caregiver perceptions about care recipient's PA

Development and binding mode assessment of N-[4-[2-propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-D-glutamic acid (BGC 945), a novel thymidylate synthase inhibitor that targets tumor cells.

N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-d-glutamic acid 1 (BGC 945, now known as ONX 0801), is a small molecule thymidylate synthase (TS) inhibitor discovered at the Institute of Cancer Research in London. It is licensed by Onyx Pharmaceuticals and is in phase 1 clinical studies. It is a novel antifolate drug resembling TS inhibitors plevitrexed and raltitrexed that combines enzymatic inhibition of thymidylate synthase with α-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through α-folate receptor (α-FR) transport. The α-FR, a cell-surface receptor glycoprotein, which is overexpressed mainly in ovarian and lung cancer tumors, has an affinity for 1 similar to that for its natural ligand, folic acid. This study describes a novel synthesis of 1, an X-ray crystal structure of its complex with Escherichia coli TS and 2'-deoxyuridine-5'-monophosphate, and a model for a similar complex with human TS

De novo designed protein inhibitors of amyloid aggregation and seeding.

Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-β (Aβ) in Alzheimer's disease (AD) and alpha-synuclein (αSyn) in Parkinson's disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, "capping" them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aβ, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in&nbsp;vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD

Structure-based inhibitors of amyloid beta core suggest a common interface with tau.

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline