Alzheimer\'s disease (AD) stands as one of the most prevalent neurodegenerative conditions, leading to cognitive impairment, with no cure and preventive measures. Misfolding and aberrant aggregation of amyloid-β (Aβ) peptides are believed to be the underlying cause of AD. These amyloid aggregates culminate in the development of toxic Aβ oligomers and subsequent accumulation of β-amyloid plaques amidst neuronal cells in the brain, marking the hallmarks of AD. Drug development for the potentially curative treatment of Alzheimer\'s is, therefore, a tremendous challenge for the scientific community. In this study, we investigate the potency of Whitlock\'s caffeine-armed molecular tweezer in combating the deleterious effects of Aβ aggregation, with special emphasis on the seven residue Aβ16-22 fragment. Extensive all-atom molecular dynamics simulations are conducted to probe the various structural and conformational transitions of the peptides in an aqueous medium in both the presence and absence of tweezers. To explore the specifics of peptide-tweezer interactions, radial distribution functions, contact number calculations, binding free energies, and 2-D kernel density plots depicting the variation of distance-angle between the aromatic planes of the peptide-tweezer pair are computed. The central hydrophobic core, particularly the aromatic Phe residues, is crucial in the development of harmful amyloid oligomers. Notably, all analyses indicate reduced interpeptide interactions in the presence of the tweezer, which is attributed to the tweezer-Phe aromatic interaction. Upon increasing the tweezer concentration, the residues of the peptide are further encased in a hydrophobic environment created by the self-aggregating tweezer cluster, leading to the segregation of the peptide residues. This is further aided by the weakening of interstrand hydrogen bonding between the peptides, thereby impeding their self-aggregation and preventing the formation of neurotoxic β-amyloid. Furthermore, the study also highlights the efficacy of the molecular tweezer in destabilizing preformed amyloid fibrils as well as hindering the aggregation of the full-length Aβ1-42 peptide.

UNASSIGNED: To explore the effect of amyloid-β peptide (Aβ) on mandibular condyle to develop a new treatment for postmenopausal women with Temporomandibular joint osteoarthritis.
UNASSIGNED: A murine bone loss model was established by ovariectomy. Microstructure parameters of the condyle were measured by microcomputed tomography before and after intraperitoneal injection with Aβ. Flow cytometry, Alizarin red staining, RT-qPCR assays, FITC/PI staining, Oil Red O staining and western blotting were used to evaluate the effect of Aβ on the osteogenic differentiation of mouse bone marrow stromal stem cells (mBMSCs).
UNASSIGNED: In vivo, condylar microstructure parameters increased. Serum osteoprotegerin and procollagen type 1 N propeptide increased in a dose-dependent manner after the injection of Aβ, which were opposite the changes observed in c-terminal telopeptides of type I collagen, tumor necrosis factor-α and the high serum level of leptin. In vitro, Aβ promoted calcium nodule formation in the cells. The expression of ALP, Runx2, osteorix and osteocalcin increased significantly. The expression of mRNAs related to the Wnt signaling pathway was significantly upregulated, which could be blocked by DKK1.
UNASSIGNED: Aβ can reverse bone loss in the mandibular condyle in ovariectomized mice through promoting the osteogenic differentiation of mBMSCs via the Wnt pathway.

Introduction: Alzheimer\'s disease (AD) is a progressive debilitating neurological disorder representing the most common neurodegenerative disease worldwide. Although the exact pathogenic mechanisms of AD remain unresolved, the presence of extracellular amyloid-β peptide 1-42 (Aβ1-42) plaques in the parenchymal and cortical brain is considered one of the hallmarks of the disease. Methods: In this work, we investigated the Aβ1-42 fibrillogenesis timeline up to 48 h of incubation, providing morphological and chemo-structural characterization of the main assemblies formed during the aggregation process of Aβ1-42, by atomic force microscopy (AFM) and surface enhanced Raman spectroscopy (SERS), respectively. Results: AFM topography evidenced the presence of characteristic protofibrils at early-stages of aggregation, which form peculiar macromolecular networks over time. SERS allowed to track the progressive variation in the secondary structure of the aggregation species involved in the fibrillogenesis and to determine when the β-sheet starts to prevail over the random coil conformation in the aggregation process. Discussion: Our research highlights the significance of investigating the early phases of fibrillogenesis to better understand the molecular pathophysiology of AD and identify potential therapeutic targets that may prevent or slow down the aggregation process.

Amyloid plaques are a major pathological hallmark involved in Alzheimer\'s disease and consist of deposits of the amyloid-β peptide (Aβ). The aggregation process of Aβ is highly complex, which leads to polymorphous aggregates with different structures. In addition to aberrant aggregation, Aβ oligomers can undergo liquid-liquid phase separation (LLPS) and form dynamic condensates. It has been hypothesized that these amyloid liquid droplets affect and modulate amyloid fibril formation. In this review, we briefly introduce the relationship between stress granules and amyloid protein aggregation that is associated with neurodegenerative diseases. Then we highlight the regulatory role of LLPS in Aβ aggregation and discuss the potential relationship between Aβ phase transition and aggregation. Furthermore, we summarize the current structures of Aβ oligomers and amyloid fibrils, which have been determined using nuclear magnetic resonance (NMR) and cryo-electron microscopy (cryo-EM). The structural variations of Aβ aggregates provide an explanation for the different levels of toxicity, shed light on the aggregation mechanism and may pave the way towards structure-based drug design for both clinical diagnosis and treatment.

Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aβ peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimer\'s disease (AD). We investigate the structure of human-derived Aβ40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro Aβ40 fibril structures. One population has an ordered N-terminal fold comprised of two β-strands stabilized by electrostatic interactions involving D1, E22, D23 and K28. This charged cluster is disrupted in the second population, which exhibits a disordered N-terminus and is favored in fibrils derived from the familial Dutch-type CAA patient. These results illustrate differences between human-derived CAA and AD fibrils, and how familial CAA mutations can guide fibril formation.

Alzheimer\'s disease (AD) is a detrimental neurodegenerative disease affecting the elderly. Clinically, it is characterized by progressive memory decline and subsequent loss of broader cognitive functions. Current drugs provide only symptomatic relief but do not have profound disease-modifying effects. There is an unmet need to identify novel pharmacological agents for AD therapy. Neuropathologically, the characteristic hallmarks of the disease are extracellular senile plaques containing amyloid β-peptides and intracellular neurofibrillary tangles containing hyperphosphorylated microtubule-associated protein tau. Simultaneously, oxidative stress, neuroinflammation and mitochondrial dysfunction in specific brain regions are early events during the process of AD pathologic changes and are associated with Aβ/tau toxicity. Here, we first summarized probable pathogenic mechanisms leading to neurodegeneration and hopefully identify pathways that serve as specific targets to improve therapy for AD. We then reviewed the mechanisms that underlie disease-modifying effects of natural polyphenols, with a focus on nuclear factor erythroid 2-related factor 2 activators for AD treatment. Lastly, we discussed challenges in the preclinical to clinical translation of natural polyphenols. In conclusion, there is evidence that natural polyphenols can be therapeutically useful in AD through their multifaceted mechanism of action. However, more clinical studies are needed to confirm these effects.

Oligomeric assemblies of the amyloid β peptide (Aβ) have been investigated for over two decades as possible neurotoxic agents in Alzheimer\'s disease. However, due to their heterogeneous and transient nature, it is not yet fully established which of the structural features of these oligomers may generate cellular damage. Here, we study distinct oligomer species formed by Aβ40 (the 40-residue form of Aβ) in the presence of four different metal ions (Al3+, Cu2+, Fe2+, and Zn2+) and show that they differ in their structure and toxicity in human neuroblastoma cells. We then describe a correlation between the size of the oligomers and their neurotoxic activity, which provides a type of structure-toxicity relationship for these Aβ40 oligomer species. These results provide insight into the possible role of metal ions in Alzheimer\'s disease by the stabilization of Aβ oligomers.

Aggregates of amyloid-β (Aβ) peptides are thought to cause Alzheimer\'s disease. Polyphenolic compounds are known to inhibit Aβ aggregation. We applied replica permutation with solute tempering (RPST) to the system of Aβ fragments, Aβ(16-22), and polyphenols to elucidate the mechanism of inhibition of Aβ aggregation. The RPST molecular dynamics simulations were performed for two polyphenols, myricetin (MYC) and rosmarinic acid (ROA). Two Aβ fragments were distant, and the number of residues forming the intermolecular β-sheet was reduced in the presence of MYC and ROA compared with that in the absence of polyphenols. MYC was found to interact with glutamic acid and phenylalanine of Aβ fragments. These interactions induce helix structure formation of Aβ fragments, making it difficult to form β-sheet. ROA interacted with glutamic acid and lysine, which reduced the hydrophilic interaction between Aβ fragments. These results indicate that these polyphenols inhibit the aggregation of Aβ fragments with different mechanisms.

Alzheimer\'s disease (AD) is the most common neurodegenerative disorder and the main cause of dementia which is characterized by a progressive cognitive decline that severely interferes with daily activities of personal life. At a pathological level, it is characterized by the accumulation of abnormal protein structures in the brain-β-amyloid (Aβ) plaques and Tau tangles-which interfere with communication between neurons and lead to their dysfunction and death. In recent years, research on AD has highlighted the critical involvement of mitochondria-the primary energy suppliers for our cells-in the onset and progression of the disease, since mitochondrial bioenergetic deficits precede the beginning of the disease and mitochondria are very sensitive to Aβ toxicity. On the other hand, if it is true that the accumulation of Aβ in the mitochondria leads to mitochondrial malfunctions, it is otherwise proven that mitochondrial dysfunction, through the generation of reactive oxygen species, causes an increase in Aβ production, by initiating a vicious cycle: there is therefore a bidirectional relationship between Aβ aggregation and mitochondrial dysfunction. Here, we focus on the latest news-but also on neglected evidence from the past-concerning the interplay between dysfunctional mitochondrial complex I, oxidative stress, and Aβ, in order to understand how their interplay is implicated in the pathogenesis of the disease.

The negative effects of periodontitis on systemic diseases, including diabetes, cardiovascular diseases, and Alzheimer\'s disease (AD), have been widely described.
This systematic review aimed to gather the current understanding of the pathophysiological mechanisms linking periodontitis to AD.
An electronic systematic search of the PubMed/MEDLINE, Scopus, and Embase databases was performed using the following PECO question: How can periodontitis or periodontal bacteria influence Alzheimer\'s disease features?\". Only preclinical studies exploring the biological links between periodontitis and AD pathology were included. This study was registered at the International Prospective Register of Systematic Reviews (PROSPERO), and the Syrcle and Camarades protocols were used to assess the risk of bias.
After a systematic screening of titles and abstracts (n = 3,307), thirty-six titles were selected for abstract reading, of which 13 were excluded (k = 1), resulting in the inclusion of 23 articles. Oral or systemic exposure to periodontopathogens or their byproducts is responsible for both in situ brain manifestations and systemic effects. Significant elevated rates of cytokines and amyloid peptides (Aβ) and derivate products were found in both serum and brain. Additionally, in infected animals, hyperphosphorylation of tau protein, hippocampal microgliosis, and neuronal death were observed. Exposure to periodontal infection negatively impairs cognitive behavior, leading to memory decline.
Systemic inflammation and brain metastatic infections induced by periodontal pathogens contribute to neuroinflammation, amyloidosis, and tau phosphorylation, leading to brain damage and subsequent cognitive impairment.