Tau, Aβ, and Network Degeneration in Alzheimer’s Disease

Tau protein is known to go through abnormal changes that cause it to accumulate in the brains of Alzheimer’s patients for yet unclear reasons. Immunotherapy using recombinant molecules (ie, molecules formed in the laboratory through genetic recombination) has emerged as a promising approach to target tau accumulation; however, many questions persist about the optimal form of anti-tau immunotherapy. We propose to compare the ability of genetically engineered antibodies targeted to the intracellular or extracellular levels to fight tau pathology in two mouse models.

Our results will provide critical insights into which method is more effective (ie, extracellular vs. intracellular) and whether the full-length antibody and not just its binding fragment is required.

Tau protein is known to go through phosphorylation and to accumulate in the brains of Alzheimer’s patients where, in this altered form, it contributes to neuronal dysfunction and death. Phosphorylation turns many protein enzymes on and off, thereby altering their function and activity, and this plays a significant role in a wide range of cellular processes. Anti-tau immunotherapy has emerged as a promising approach to target this pathological conversion, but many questions regarding the optimal form of anti-tau immunotherapy remain open.

In our search for potential modifiers of Alzheimer’s disease (AD) pathology in mouse models, we have developed a “somatic brain transgenics” paradigm, consisting of genes packaged into adeno-associated viral vectors and delivered to the brains of newborn mice by injection.

We propose to compare the ability of recombinant intracellular and extracellular antibodies to attenuate tau pathology in two mouse models.

Results from these studies will provide critical insights into a) whether targeting tau in the extracellular vs. intracellular compartment is more efficacious and, b) whether full length antibody and not just its binding fragment antibody effector functions are required.