The present invention relates to the design and development of recombinant protein for the delivery of silencer RNA complex to mediate RNA interference since it represents a novel therapeutic approach to modulate several neurodegenerative disease-related genes across the blood-brain barrier (BBB). To overcome challenges due to this barrier for biologics and other biological complex, the present invention describes a method wherein peptide having sequence GGGGHLNILSTLWKYRC represented by SEQ ID NO. 9 known to target specific gangliosides was linked to a double-stranded RNA binding protein to bind and deliver silencer RNA to the brain parenchyma. The designed fusion protein comprising a double-stranded RNA-binding domain (dsRBD) of human Trans Activation response element (TAR) RNA Binding Protein (TARBP2) and a brain targeting peptide sequence that binds GM1. Conformation-specific binding of TARBP2 domain to silencer RNA results in the formation of homogenous serum-stable complex with GM1 targeting potential. Uptake of the complex in neural cells reveals selective requirement of GM1 for entry. Remarkably, the invention pertains to the systemic delivery of the complex comprising TARBP-BTP and silencer RNA in APP-PS1 mouse model of Alzheimer's disease (AD) led to distinctive localization primarily in the cerebral hemisphere in the hippocampus and brain cortex and in principle can work across other mammalian CNS targets. Further, the delivery of silencer-RNA mediated by brain targeting peptide fusion led to significant knockdown of BACE1, a therapeutic protease target in both APP-PS1 and wild type C57BL/6 mice. The invention establishes the emergent importance of fusion proteins in delivering therapeutic siRNA as a simple complex to brain tissues to treat neurodegenerative diseases besides Alzheimer's disease (AD). The complex is also useful to study gene function of hitherto unidentified genes/interplay of genes in mammalian systems and central nervous system.

The present invention relates to bispecific antibodies that bind to transferrin receptor and BACE1 and methods of using the same.

Described herein are methods of identifying a mammal having a neurological disease or disorder, such as AD or MCI, or at risk for developing a neurological disease or disorder, such as AD or MCI. Provided herein are also methods of monitoring the progression of a neurological disease or disorder in a patient or monitoring the effectiveness of therapeutic agent or treatment of a patient having a neurological disease or disorder.

Provided herein are compositions comprising a nucleic acid encoding amyloid-beta precursor protein and/or a nucleic acid encoding presenilin-1, cells comprising the compositions, animals comprising the compositions, methods of making the cells and animals, methods of modeling Alzheimer's disease, methods of assessing a therapeutic candidate for the treatment of Alzheimer's disease or amelioration of a symptom or phenotype of Alzheimer's disease, and methods of assessing a therapeutic candidate for the prevention of Alzheimer's disease or prevention of a symptom or phenotype of Alzheimer's disease.

The present disclosure provides, among other things, methods for using presenilin based gene therapy to treat neurodegenerative dementia including, but not limited to Alzheimers disease, frontotemporal dementia, frontotemporal lobar degeneration, Picks disease, Lewy body dementia, memory loss, and cognitive impairment including mild cognitive impairment (MCI).