Described herein is a method for treating Alzheimer's disease (AD) by selective silencing of the amyloid precursor protein (APP) using Cas9 nuclease gene editing. Methods of making and using genetic constructs comprising a Cas9 nuclease and a sequence encoding guide RNA (gRNA) specific to APP capable of truncating the C-terminus of APP, as well as compositions comprising these constructs, are provided.

The present disclosure provides methods to quantify tau phosphorylation at specific amino acid residues, using blood samples, to predict time to onset of mild cognitive impairment due to Alzheimer's disease, stage Alzheimer's disease, guide treatment decisions, select subjects for clinical trials, and evaluate the clinical efficacy of certain therapeutic interventions.

A substance that can be a substitute for amylospheroids (ASPD) and a method for analyzing ASPD are provided. Viewed from one aspect, the present disclosure relates to a substance in which amyloid-β protein (Aβ) is cross-linked with a cross-linking agent that has a spacer arm length of between 4 Å and 50 Å inclusive or a cross-linking agent that has, as a spacer arm, not less than 1 and not more than 13 groups that are an oxyethylene group(s) (—CH.sub.2CH.sub.2O—) and/or an oxypropylene group(s) (—CH.sub.2CH.sub.2CH.sub.3O—). Viewed from another aspect, the present disclosure relates to a method for analyzing ASPD using the substance as a reference material.

A brain-penetrating composition of amyloid-ß binding peptide is disclosed. This may be useful in the treatment of Alzheimer's disease, for example as a bifunctional molecule, comprising a blood-brain barrier crossing antibody and an amyloid-ß targeting peptide linked via an Fc fragment that is able to transmigrate across the blood-brain barrier into the brain, and compositions comprising same. Methods of using this composition for treating Alzheimer's disease are disclosed.

A facilitated method for use in efficient delivery of a pharmaceutical composition over a tissue such as the blood brain barrier and into neurons in the CNS for the treatment of Alzheimer's disease in a mammal, including man is provided. The method is comprising the steps of administrating a therapeutically effective amount of the isolated recombinant Bri2 BRICHOS and lipid microbubbles and enables an increased amount of the isolated recombinant protein to reach the brain to efficiently combat Aβ42 neurotoxicity.

Furthermore, a method for use in enhanced delivery of proteins comprising Bri2 BRICHOS and variants thereof over the blood-brain barrier, facilitating treatment and/or diagnostics of Alzheimer's disease and other neurological diseases is described herein. The method is comprising the steps of administrating a therapeutically effective amount of proteins comprising Bri2 BRICHOS and variants thereof as a first protein moiety coupled to another (non-Bri2) second protein or polypeptide moiety and optionally lipid microbubbles, in the absence of ultrasound treatment.

This disclosure relates to a method of decreasing concentration of tau (τ) protein and/or phosphorylated tau (τ) protein in a target cell of a human or animal subject having Alzheimer's Disease (AD). The disclosure extends to use of biopharmaceutical agents including (i). 37 kDa/67 kDa laminin receptor precursor/high affinity laminin receptor (LRP/LR) and/or a fragment thereof, or (ii). a transfecting agent for the expression of LRP/LR, for use in treating Alzheimer's Disease (AD).

Disclosed are a novel protein variant for controlling fibrosis of amyloid beta and a composition for treating neurodegenerative diseases using the same.

The present disclosure provides a genetically modified mouse comprising a genomic nucleic acid encoding human APOE4, a genomic nucleic acid encoding mouse TREM2 modified to include a R47H substitution, and at least one genomic modification selected from the group consisting of: (a) a genomic nucleic acid encoding mouse ABCA7 modified to include an A 1541 G substitution; (b) a genomic nucleic acid encoding mouse APP modified to include G60IR, F606Y, and R609H substitutions; (c) a genomic nucleic acid encoding mouse PLCG2 modified to include a M28L substitution; (d) a genomic nucleic acid encoding mouse MTHFR modified to include a A262V substitution; (e) an inactivated Ceacaml allele; and (f) an inactivated II1rap allele. Methods of producing the genetically modified mouse and methods of using the genetically modified mouse are also provided.

Provided herein are modified immunoglobulins comprising an amyloid reactive peptide joined to an antibody, as well as humanized antibodies that bind to human amyloid fibrils and antibody-peptide fusion proteins. Also provided herein are methods of treating amyloid-based diseases by administering a modified immunoglobulin, humanized antibody, or antibody-peptide fusion protein.

The subject matter disclosed herein relates to methods of identifying pharmacophores and inhibitors against protein aggregation. The present disclosure also provides pharmacophores themselves and medical uses of agents in the treatment of diseases associated with protein aggregation.