Highly selective detection of tau oligomers in biological fluids for the diagnosis of Alzheimer's Disease

ABSTRACT This proposal is for a phase I II fast track project for the STTR program with the main goal to develop a test for high sensitive detection of tau oligomers in biological fluidswhich could be used for the biochemical diagnosis of Alzheimerandapos s diseaseADand related tauopathiesAD is the most common dementia in the elderly population and one of the leading causes of death in the developed worldOne of the main problems in AD is the lack of an earlysensitive and objective laboratory diagnosis to identify individuals that will develop the disease before substantial brain damageCompelling evidences point that the hallmark event in AD is the misfoldingaggregation and brain accumulation of amyloid betaAand tau proteinsRecent evidences suggest that Apathology is the primary driving force of the disease initiationbut this is accomplished by induction of tau hyperphosphorylationmisfolding and aggregationleading to the neurodegenerative cascadeTau aggregation follows a seeding nucleation mechanism and involves several intermediatesincluding soluble oligomers and protofibrilsRecent evidence has shown that tau oligomers are circulating in biological fluids and these structures appear to be key for inducing brain degeneration in ADOur working hypothesis is that detection of misfolded tau oligomers circulating in blood may be the basis for an early biochemical diagnosis for ADOur approach is to use the functional property of misfolded oligomers to seed the aggregation of the monomeric protein as a way to detect themFor this purposewe have developed the protein misfolding cyclic amplificationPMCAwhich represent a platform technology to detect very small quantities of seeding competent misfolded oligomeric proteins associated with various protein misfolding diseasesCurrentlyPMCA has been adapted to detect misfolded prion protein implicated in prion diseases in various biological fluidsincluding blood and urine and more recently soluble oligomers composed of Aandsynuclein in cerebrospinal fluidCSFof patients affected by AD and Parkinsonandapos s diseaserespectivelyThe major goal of this project is to adapt the PMCA technology for specific and highly sensitive detection of misfolded tau oligomers in human CSF and blood plasmaperform studies of specificity and sensitivity using large number of samples coming from patients affected by AD and other tauopathies as well as to evaluate the utility of tau PMCA for monitoring disease progressionThe results generated in this project may lead to the first biochemical test for diagnosis of ADThe studies included in this project will constitute the basis for regulatory approval of the test that Amprion will commercialize NARRATIVE Development of a biochemical assay for the sensitiveearly and non invasive diagnosis of Alzheimerandapos s disease is a top medical priorityessential to permit efficient treatment of this devastating diseaseThis project proposes to develop the protein misfolding cyclic amplificationPMCAtechnology to detect with high sensitivity and specificity tau oligomers which are considered the key molecules responsible for neurodegeneration in ADIn this project we have put together the relevant technical and business expertise and secured the availability to key samples to permit the successful developmentvalidation and approval of the test