Compelling evidence suggests that oligomeric A? plays a crucial neurotoxic and synaptotoxic role in Alzheimer?s disease (AD), and that hyperphosphorylation of the microtubule associated protein (MAP) tau mediates or facilitates A? toxicity. The nature of the link between A? and tau in causing AD has however remained largely unexplained, casting doubt on the amyloid hypothesis itself. In neurons, control of microtubule dynamics and tubulin modifications that accumulate on stable microtubules is necessary for multiple homeostatic and regulated functions, including long-distance transport and synaptic activity. Thus, regulation of the ratio between stable and dynamic microtubules is crucial to avoid disease. To date, almost nothingisknownaboutwhetherinductionofhyperstableandmodifiedmicrotubulesisaprimaryactivityofA? thatcontributestotauhyperphosphorylationandsynaptotoxicity. We have preliminary data that detyrosinated tubulin is enriched in hippocampal tissue of AD patients andanimalmodelsofAD,andthataccumulationofdetyrosinatedtubulinmayinducetauhyperphosphorylation in primary neurons. In addition, we found that acute incubation of primary neurons with oligomeric A?1-42 generated detyrosinated MTs by transient microtubule hyperstabilization. Inhibition of the formin mDia1, a positive regulator of microtubule stability, suppressed this activity, affected tau hyperphosphorylation and rescuedsynaptotoxicityinducedbyA?invitro.Theoverallobjectiveofthisproposalistotesttheparadigm- shifting hypothesis that oligomeric A? acutely induces hyperstable detyrosinated microtubules through the activation of mDia1, and that tubulin detyrosination contributes to tau hyperphosphorylation as part of a negative feedback loop to maintain appropriate levels of dynamic and unmodified microtubules. In this proposal,wewillcharacterizethenatureofthismicrotubulehyperstabilizationinneuritesandatsynapticsites, and investigate whether APP and integrin signaling pathways are required for this A?-driven microtubule activity. In addition, we will test the role of mDia1 in mediating A?-synaptotoxicity in vivo, and examine the molecularmechanismsbywhichmDia1-synaptotoxicityoccurs. Ourproposalreliesonamultidisciplinaryefforttotestapathogenicroleforformin-mediatedregulation of microtubule stability by A? and the involvement of tubulin detyrosination in the induction of tau hyperphosphorylation and neuronal injury. Our studies will test a unifying theory for the pathogenesis of AD and examine the role for mDia1 and possibly other formins as potential targets in drug therapies aimed at rescuingA?andphospho-tautoxicityinAD.

Public Health Relevance

Alzheimer?s disease is associated with altered handling of a peptide known as A? and a microtubule binding protein, tau. The relationship between the disease protein conformations and the microtubule cytoskeleton, and how this may cause Alzheimer?s disease is unknown, but of fundamental importance for developingeffectivenewtherapies.Werecentlydiscoveredthatanimportantmissinglinkintoxicmechanisms that lead to Alzheimer?s disease might be mediated by acute A? induction of selective microtubule hyperstabilization through activation of a class of proteins known as formins, particularly the formin mDia1, which acts as a positive regulator of microtubule stability. Our proposal is a multidisciplinary effort to test a synaptotoxic role for mDia1-mediated regulation of microtubule stability by A? and the involvement of tubulin post-translational modifications associated with stable microtubules in the induction of tau hyperphosphorylationandtheneuronalinjuryofAlzheimer?sdisease.Ourstudieswilltestaunifyingtheoryfor thepathogenesisofAlzheimer?sdiseaseandexaminetheroleforforminsaspotentialtargetsindrugtherapies aimedatrescuingA?andphospho-tautoxicityinAlzheimer?sdisease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG050658-03
Application #
9516846
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Opanashuk, Lisa A
Project Start
2016-09-01
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Qu, Xiaoyi; Yuan, Feng Ning; Corona, Carlo et al. (2017) Stabilization of dynamic microtubules by mDia1 drives Tau-dependent A?1-42 synaptotoxicity. J Cell Biol 216:3161-3178