Targeting Endosomal dysfunction as a new source of biomarkers for Alzheimer's disease

Endosomal dysfunction is a well-accepted cell biological feature in Alzheimer’s disease (AD). However,
biomarkers reflecting endosomal traffic defects are still lacking. Current imaging and cerebrospinal fluid (CSF)
AD biomarkers focus primarily on the histopathology of the disease—that is, biomarkers that are linked to
neurofibrillary tangles and amyloid plaques. This proposal is designed to expand this focus to develop
biomarkers of the ‘cell biology’ of AD. Such biomarkers could potentially accelerate drug discovery, as
therapeutic interventions are currently being developed that target endosomal trafficking defects in AD.
Genetic and cell biology studies have previously linked the endosomal trafficking assembly Retromer to
AD pathology. Most notable are deficiencies and rare mutations in retromer’s core protein, VPS35, and
retromer’s receptor, SORL1. Depletion of either VPS35 or SORL1 mimics the core cytopathology in AD, enlarged
endosomes in neurons, with concomitant mis-trafficking of endosomal cargoes.
In an effort to characterize defects in the endocytic pathway resulting from retromer dysfunction, we recently
completed a proteomic screen of CSF of VPS35 knock-out (KO) mice and control littermates. Among the proteins found elevated in the CSF of VPS35 KO mice were well established β-secretase BACE1 substrates, includingAPP (Amyloid Precursor Protein); APLP1/2 (Amyloid Beta Precursor Like Proteins 1 and 2); and CHL1 (Neuralcell adhesion molecule L1-like protein). Two of these proteins --APLP1 and CHL1-- were further validated inmouse CSF, and human CSF from cognitively healthy participants and prodromal AD patients. Collectively, our studies suggest BACE1 substrates as potential biomarkers of retromer-dependent endosomal dysfunction.
However, since VPS35 is implicated in other neurodegenerative disorders, including Parkinson’s disease (PD),
these new biomarkers may not be specific to AD. Therefore, relying on these exciting findings, but moving
towards the development of a panel of biomarkers reflecting endosomal trafficking defects that are specific to
AD, we will examine SORL1 mouse models and human pluripotent stem cell (hPSC) SORL1-derived neurons
as a new source of biomarkers of endosomal trafficking. We will also investigate exosomes as an additional
source of biomarkers of endosomal defects. Lastly, since Sorl1 protein levels are altered in AD and CSF from
AD patients, we will examine SORL1 CSF levels as a potential biomarker for AD. Completion of this study will
provide evidence that SORL1-dependent endosomal trafficking is a new source of biomarkers for AD.
Moreover, we predict that the extensive studies here proposed will identify a unique and specific
endosomal biomarker of the “cell biology” of AD.

Grant Number: 5R01AG071868-05
NIH Institute/Center: NIH
Principal Investigator: Sabrina Alves Simoes Spassov