Mechanisms of Tau Structural Changes and Aggregation Upon Tau Hyperphosphorylation
Abstract
Alzheimer s disease (AD) is characterized by changes in the structure of the protein tau. Tau natively is a soluble protein that binds microtubules and stabilizes the elongated structure of neurons, enabling the proper function of neurons. In contrast, in AD and in traumatic brain injury (TBI)-induced chronic traumatic encephalopathy (CTE) and early onset AD, tau changes to an aggregated protein that forms the neurofibrillary tangles (NFTs) that are hallmarks of AD and are observed in CTE. The change in structure of tau in disease is accompanied by a change in the phosphorylation of tau, that is, the addition of a number of phosphate groups to tau (known as hyperphosphorylation of tau) by proteins called protein kinases. The hyperphosphorylation of tau leads to changes in the structure of tau, including the generation of forms of tau that aggregate. In addition, recent data have indicated that aggregates of hyperphosphorylated tau are capable of spreading disease from one neuron to another, leading to transmission and spread of the disease from one area of the brain to another. Notably, in TBI-induced CTE and early onset AD, this seeding process is more potent than in typical age-related AD, resulting in rapid appearance of hyperphosphorylated tau and rapid appearance and transmission of disease symptoms. Due to technical challenges that make it difficult to prepare hyperphosphorylated tau for in-depth analysis, the specific details of how hyperphosphorylation changes the structure of tau are not well understood. In particular, it is not well understood how different, specific patterns of phosphorylation, including potentially patterns that might be particularly potent in seeding development and spread of disease, affect the structure, function, aggregation, and disease transmission of tau. In order to understand how AD develops and, in particular, to understand the early onset of neurodegeneration in TBI-associated AD and CTE, we will develop approaches to synthesize versions of tau that have defined patterns of hyperphosphorylation. We will examine the differential effects of these hyperphosphorylated tau proteins to change the structure of tau, the solubility of tau, and the ability of tau to induce or transmit aggregated tau, in a manner consistent with the onset and transmission of disease. In addition, inhibitors of tau kinases have the potential to treat or prevent AD and CTE. Thus, this work can be used both to understand the basic biology, development, and progression of AD and in the development of new therapeutics to treat AD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510375
Entities
People
- Neal J Zondlo
Organizations
- United States Army
- University of Delaware