Therapeutic targeting of impaired lysosomal flux in Alzheimer's disease

There are currently no effective treatments for Alzheimer's disease (AD). Novel approaches are urgently needed.
Innovative systems that increase the clearance of disease-associated proteins in and around brain cells are one such approach. Increased clearance of these proteins via lysosomal flux show extremely encouraging results in AD animal models, clearing the two hallmark brain changes that define AD, deposition of amyloid-beta-protein (Abeta) and tau.
However, therapeutic targets which will selectively modify lysosomal flux to prevent these brain changes are lacking. Our previous research indicates that the lysosomal Ca2+ release channel protein, TRPML1, has major potential as such a target.
This proposal will use our multidisciplinary expertise to determine the therapeutic potential of TRPML1 in AD. TRPML1 is easily targetable and selectively activated/inactivated by lipid molecules called the phosphoinositides (PI), specifically PI(3,5)P2 and PI(4,5)P2, respectively.
Many previously identified AD risk genes bind to PI(4,5)P2 (including ApoE4, PICALM, BIN1, CD2AP). Another AD risk gene can alter PI(4,5)P2 metabolism (INN5PD). We will test the hypothesis that these previously identified risk genes regulate phosphinositide activity to contribute to AD pathology by altering TRPML-1 mediated lysosomal flux, and determine whether targeting this TRPML1 defect offers therapeutic potential for AD. Combining a multi-disciplined approach involving our expertise in AD neuropathology, TRPML1 function, lysosomal flux and AD genetics, this research presents an exciting opportunity to develop novel disease-modifying therapeutic/diagnostic platforms with selective innovative targeting of lysosomal flux defects to combat AD pathogenesis in populations worldwide.

We propose that TRPML1 becomes dysfunctional in the AD brain, and via age-related alterations in AD risk genes, and that modulating TRPML1 function will clear both Abeta and tau pathology. This highly original approach builds on solid foundations from the complementary strengths of all members of the collaborating teams; identifying risk genes for AD and early changes in AD brain systems that directly affect EAL function, as well as specific defects in the TRPML1 and lysosomal system that negatively affect the catabolism of APP in AD models.

We hypothesise that PI-mediated control of TRPML1-mediated lysosomal flux, which is critical for functional neuronal longevity, becomes progressively defective in AD brain and causes failure in APP/Abeta and tau clearance. This ties in with our complementary research findings in AD pathology, lysosomal systems and AD genetics. Specifically, re: genetics our realisation that a number of genes (APOE4, PICALM, BIN1 and CD2AP) that confer risk for developing late-onset AD (LOAD), have direct binding sites and regulate PI(4,5)P2 or regulate PI(3,5)P2 /PI(4,5)P2
levels (INPP5D), the major molecular switch that turns TRPML1 on / off respectively. Together, this provides the progressive possibility that these risk genes via their regulation of PI(3,5)P2 /PI(4,5)P2, alter TRPML1 function in AD. This is a totally original and transformative approach linking PI system control to lysosomal defects in AD as a major new approach to understand genetic predisposition, diagnosis and treatment of AD.

Who might benefit from this research?

A thorough exploitation programme will be established to maximise effective knowledge transfer of our research outcomes to key groups (patient groups, research scientists, healthcare
professionals, technologists, industry, policy makers and educators). This will maximise future progress of the project outcomes, including following project completion, integrated with funding applications to national, EU and international agencies, and industrial engagement.

How might they benefit from this research?

The impact of the project will mainly focus on the research scientist who will benefit directly from the research. The results of the research will then be communicated to other parties including patient groups, healthcare professionals, and such, who will benefit from an improved understanding of the mechanisms of disease in Alzheimer's pathology. Further impact will include improvements to future research into therapeutic targets for disease, and focus of resources for both the scientific community and medical community.

Exploitation and dissemination plans will be discussed and planned with agreement by both principal investigators and teams prior to project commencement to ensure maximal impact. A draft implementation plan detailing how to manage the exploitation of the results will be prepared before and at the end of year 1 and updated during the remainder of the project. Exploitation and intellectual property management will involve all partners. Should patentable discoveries result from this work, the collaborating groups, and their institutions have the expertise to ensure that appropriate benefits are retained. The successful management will coordinate all exploitation-related issues, including IP, patents, licences, and transfer of material between partners. When appropriate, patents will be applied for prior to publication by partners involved. The IP and Technology Transfer Offices will guide the exploitation strategy in
each collaborating institution.