New Nanoprobes for MR Imaging of TrkB in Alzheimer's Disease

Exqor Technologies, Inc., Boston MA

Investigators

Abstract

Alzheimer's disease (AD) is a chronic and disabling brain disease characterized by amyloid beta (Aβ) and tau accumulation, and progressive loss of synapses and neurons that are associated with low brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) levels. Recent studies show deficient BDNF-TrkB signaling mediates amyloid-β and tau induced neurotoxicity, reduced neurogenesis, synaptic dysfunction, and memory deficits in AD. Also, BDNF and TrkB hippocampal (HIP) gene expressions are predictors of neuritic plaque and neurofibrillary tangle pathology. Postmortem studies showed decreased HIP levels of TrkB in AD patients that correlated with their cognitive performance and neuropathology. Thus, early detection of decreased TrkB expression; which is implicated in impaired neurogenesis, synaptic damage and neuronal death; is critical for the rapid prevention and treatment of AD. New TrkB radioligands are currently being developed for PET but they are not specific for TrkB and cannot easily cross the BBB. Positron emission tomography (PET) has high sensitivity for receptor imaging but is limited by low spatial resolution and the limited availability of PET techniques. This application's goal is to develop non-radioactive nanoprobes that can be used for imaging of TrkB with conventional MRI scanners that are available in many more clinical settings than PET. A two-part TrkB-targeted nanoprobe (TNP<100 nm) will be designed. One part is a protein carrier containing a widely used MRI gadolinium contrast agent (Vitaliano at al. 2012). ExQor's patented nanocarrier is constructed out of clathrin, a naturally occurring protein the body uses for transporting materials inside cells. The second component will be the mature form of BDNF (mBDNF) that binds with high affinity and specificity to TrkB. mBDNF will be attached to the clathrin carrier by polyethylene glycol (PEG) molecules. In Phase 1 of the SBIR, a series of studies will ascertain NP uniformity and stability, plus NP affinity and specificity for TrkB in vitro and in vivo. In Phase 2, the feasibility of this MRI tool to detect TrkB expression and track progression of the disease will be demonstrated ex vivo and in vivo in a mouse model of AD. We expect to detect early decreases in TrkB associated with impaired HIP neurogenesis before Aβ/tau pathology. We also expect to show the stepwise lowering of HIP CA1 TrkB with progression of the disease that is associated with Aβ and tau accumulations, and synaptic and neuronal damage. Especially important for patients with AD, the new non-radioactive NPs may be used for early diagnosis of AD and regular monitoring of disease progression and the recovery process. This project may provide tools/techniques for molecular brain imaging that could have similar sensitivity to PET but can be used repeatedly for biomarker detection in AD. The commercial significance is in filling an unmet medical need for an imaging biomarker for early diagnosis of AD. This new nanotechnology may have utility as an agent to predict susceptibility and resilience to AD, enhance diagnosis/prognosis and may help evaluate the effectiveness of drugs aimed to treat AD.