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

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 fluids, which could be
used for the biochemical diagnosis of Alzheimer’s disease (AD) and related tauopathies. AD is
the most common dementia in the elderly population and one of the leading causes of death in
the developed world. One of the main problems in AD is the lack of an early, sensitive and
objective laboratory diagnosis to identify individuals that will develop the disease before
substantial brain damage. Compelling evidences point that the hallmark event in AD is the
misfolding, aggregation and brain accumulation of amyloid-beta (Aβ) and tau proteins. Recent
evidences suggest that Aβ pathology is the primary driving force of the disease initiation, but
this is accomplished by induction of tau hyperphosphorylation, misfolding and aggregation,
leading to the neurodegenerative cascade. Tau aggregation follows a seeding-nucleation
mechanism and involves several intermediates, including soluble oligomers and protofibrils.
Recent evidence has shown that tau oligomers are circulating in biological fluids and these
structures appear to be key for inducing brain degeneration in AD. Our working hypothesis is
that detection of misfolded tau oligomers circulating in blood may be the basis for an early
biochemical diagnosis for AD. Our approach is to use the functional property of misfolded
oligomers to seed the aggregation of the monomeric protein as a way to detect them. For this
purpose, we have developed the protein misfolding cyclic amplification (PMCA), which
represent a platform technology to detect very small quantities of seeding-competent misfolded
oligomeric proteins associated with various protein misfolding diseases. Currently, PMCA has
been adapted to detect misfolded prion protein implicated in prion diseases in various biological
fluids, including blood and urine and more recently soluble oligomers composed of Aβ and α-
synuclein in cerebrospinal fluid (CSF) of patients affected by AD and Parkinson’s disease,
respectively. The 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 plasma, perform
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 progression. The results generated in this project may lead to the first
biochemical test for diagnosis of AD. The studies included in this project will constitute the basis
for regulatory approval of the test that Amprion will commercialize.Development of a biochemical assay for the sensitive, early and non-invasive diagnosis of
Alzheimer’s disease is a top medical priority, essential to permit efficient treatment of this
devastating disease. This project proposes to develop the protein misfolding cyclic amplification
(PMCA) technology to detect with high sensitivity and specificity tau oligomers which are
considered the key molecules responsible for neurodegeneration in AD. In this project we have
put together the relevant technical and business expertise and secured the availability to key
samples to permit the successful development, validation and approval of the test.