ABSTRACT
The synthesis of well-defined cyclic polymers is crucial to exploring applications spanning engineering, energy, and biomedicine. These materials lack chain-ends and are therefore imbued with unique bulk properties. Despite recent advancements, the general methodology for controlled cyclic polymer synthesis via ring-expansion metathesis polymerization (REMP) remains challenging. Low initiator activity leads to high molar mass polymers at short reaction times that subsequently "evolve" to smaller polymeric products. In this work, we demonstrate that in situ addition of pyridine to the tethered ruthenium-benzylidene REMP initiator CB6 increases ancillary ligand lability to synthesize controlled and low dispersity cyclic poly(norbornene) on a short time scale without relying on molar mass evolution events.
ABSTRACT
Modulation of the amyloid-ß (Aß) trafficking pathway heralds a new therapeutic frontier for Alzheimer's disease (AD). As CD74 binds to the amyloid-ß precursor protein (APP) and can suppresses Aß processing, we investigated whether recombinant adeno-associated virus (AAV) delivery of CD74 could reduce Aß production and affect disease outcomes. This idea was tested in a mouse AD model. Cotransduction of AAV-tetracycline-controlled transactivator (tTA) and AAV-tet-response element (TRE)-CD74 resulted in CD74 expression, reduced Aß production in mouse neurons containing the human APP with familial AD-linked mutations. Stereotaxic injection of AAV-TRE-GFP or CD74 into the hippocampi of an AD mouse, defined as a TgCRND8 × calmodulin-dependent protein kinase II derived promoter-tTA double-transgenic, reduced Aß loads and pyramidal neuronal Aß accumulation in the hippocampus. Immunofluorescent studies showed that APP colocalization with Lamp1 was increased in CD74-expressing neurons. Moreover, Morris water maze tasks demonstrated that mice treated with AAV-TRE-CD74 showed improved learning and memory compared to AAV-TRE-GFP control animals. These results support the idea that CD74-induced alteration of Aß processing could improve AD-associated memory deficits as shown in mouse models of human disease.
Subject(s)
Alzheimer Disease/therapy , Amyloid beta-Protein Precursor/metabolism , Antigens, Differentiation, B-Lymphocyte/genetics , Histocompatibility Antigens Class II/genetics , Neurons/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/psychology , Amyloid beta-Protein Precursor/physiology , Amyloidosis/metabolism , Animals , Cells, Cultured , Dependovirus , Disease Models, Animal , Female , Genetic Therapy , Genetic Vectors/therapeutic use , Hippocampus/metabolism , Hippocampus/surgery , Humans , Lysosomal Membrane Proteins/metabolism , Male , Maze Learning , Memory , Mice , Mice, Transgenic , Microinjections/methods , Stereotaxic TechniquesABSTRACT
Aberrations in hippocampal neurogenesis are associated with learning and memory, synaptic plasticity and neurodegeneration in Alzheimer's disease (AD). However, the linkage between them, ß-amyloidosis and neuroinflammation is not well understood. To this end, we generated a mouse overexpressing familial AD (FAD) mutant human presenilin-1 (PS1) crossed with a knockout (KO) of the CC-chemokine ligand 2 (CCL2) gene. The PS1/CCL2KO mice developed robust age-dependent deficits in hippocampal neurogenesis associated with impairments in learning and memory, synaptic plasticity and long-term potentiation. Neurogliogenesis gene profiling supported ß-amyloid independent pathways for FAD-associated deficits in hippocampal neurogenesis. We conclude that these PS1/CCL2KO mice are suitable for studies linking host genetics, immunity and hippocampal function.