1.C.50.1.1
Alzheimer''s disease (AD) amyloid β-protein (amino acids 1-42) (Abeta protein or AβP or Aβ42).  Aβ pores may consist of tetrameric and hexameric beta-sheet subunits (Strodel et al. 2010).  Residues 22 - 35 in the peptide binds cholesterol to form Ca²⁺-permeable pores (Di Scala et al. 2014).  Cholesterol promotes the insertion of Abeta in the plasma membrane, induces alpha-helical structure formation, and forces the peptide to adopt a tilted topology that favours oligomerization. Bexarotene, an amphipathic drug for the treatment of neurodegenerative diseases, competes with cholesterol for binding to Abeta and prevents oligomeric channel formation (Di Scala et al. 2014). The beta-amyloid protein is involved in the activation of the nAChRalpha7 receptor (Hassan et al. 2019). Tryptophan enantiomers (d/l-Trp) introduced into artificial nanochannels regulate the chiral selective transport of Abeta proteins; the l-Trp channel shows selectivity for the transport of Abeta protein (Zhu et al. 2020). The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, mGluR5 exhibits distinct sex-dependent profiles (Abd-Elrahman et al. 2020). mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aβ-mGluR5 interaction is not depend on estrogen, but rather Aβ interaction with cellular prion protein (PrP^C), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aβ oligomers, and PrP^C was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aβ pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aβ oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. mGluR5 does not contribute to Aβ pathology in females, highlighting the complexity of mGluR5 pharmacology and Aβ signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics (Abd-Elrahman et al. 2020). Proteins associated with or anchored to the plasma membrane are associated with cerebrospinal fluid biomarkers of amyloid and tau pathology in AD (Remnestål et al. 2021). The architecture of the Alzheimer's A beta P ion channel pore has been determined (Arispe 2004). A transmembrane annular polymeric structure may be responsible for the ion channel properties of the membrane-bound A beta P (Arispe 2004). Arispe 2004 synthesized peptides that encompass the histidine dyad (H-H) hypothesized to line the pore and showed that peptides designed to most closely match the proposed pore are the most effective at blocking ion currents through the membrane-incorporated A beta P channel. Abeta) proteins can form ion pores in the cell membrane, and the structure of the transmembrane domain of Abeta ion channels is known. Substances that block or inhibit the formation of Abeta ion channels are known, and zinc ions are considered as potential inhibitors of AD (Kim et al. 2021).  The spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns (Jin et al. 2022). The folding/misfolding of membrane-permiable Amyloid beta (Abeta) peptides is likely associated with advancing stages of Alzheimer's disease (AD) by disrupting Ca²⁺ homeostasis (Ngo et al. 2023). The aggregation of four TMS Abeta(17-42) peptides suggested that the secondary structures of transmembrane Abeta peptides tends to have different propensities compared to those in solution. The residues favorably forming beta-structure were interleaved by residues rigidly adopting turn-structure. A combination of beta and turn regions likely forms a pore structure. Six morphologies of 4Abeta were found over the free energy landscape and clustering analyses. Among these, the morphologies include (1) Abeta binding onto the membrane surface and three transmembrane Abeta; (2) three helical and coil transmembrane Abeta; (3) four helical transmembrane Abeta; (4) three helical and one beta-hairpin transmembrane Abeta; (5) two helical and two beta-strand transmembrane Abeta; and (6) three beta-strand and one helical transmembrane Abd-Elrahman et al. 2020). mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aβ-mGluR5 interaction is not depend on estrogen, but rather Aβ interaction with cellular prion protein (PrP^C), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aβ oligomers, and PrP^C was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aβ pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aβ oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. mGluR5 does not contribute to Aβ pathology in females, highlighting the complexity of mGluR5 pharmacology and Aβ signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics (Abd-Elrahman et al. 2020). Proteins associated with or anchored to the plasma membrane are associated with cerebrospinal fluid biomarkers of amyloid and tau pathology in AD (Remnestål et al. 2021). The architecture of the Alzheimer's A beta P ion channel pore has been determined (Arispe 2004). A transmembrane annular polymeric structure may be responsible for the ion channel properties of the membrane-bound A beta P (Arispe 2004). Arispe 2004 synthesized peptides that encompass the histidine dyad (H-H) hypothesized to line the pore and showed that peptides designed to most closely match the proposed pore are the most effective at blocking ion currents through the membrane-incorporated A beta P channel. Abeta) proteins can form ion pores in the cell membrane, and the structure of the transmembrane domain of Abeta ion channels is known. Substances that block or inhibit the formation of Abeta ion channels are known, and zinc ions are considered as potential inhibitors of AD (Kim et al. 2021).  The spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns (Jin et al. 2022). The folding/misfolding of membrane-permiable Amyloid beta (Abeta) peptides is likely associated with advancing stages of Alzheimer's disease (AD) by disrupting Ca²⁺ homeostasis (Ngo et al. 2023). The aggregation of four TMS Abeta(17-42) peptides suggested that the secondary structures of transmembrane Abeta peptides tends to have different propensities compared to those in solution. The residues favorably forming beta-structure were interleaved by residues rigidly adopting turn-structure. A combination of beta and turn regions likely forms a pore structure. Six morphologies of 4Abeta were found over the free energy landscape and clustering analyses. Among these, the morphologies include (1) Abeta binding onto the membrane surface and three transmembrane Abeta; (2) three helical and coil transmembrane Abeta; (3) four helical transmembrane Abeta; (4) three helical and one beta-hairpin transmembrane Abeta; (5) two helical and two beta-strand transmembrane Abeta; and (6) three beta-strand and one helical transmembrane Abeta (Ngo et al. 2023).