Investigate the utility of APLP1 as an endosomal biomarker for Alzheimer's Disease in Down Syndrome

SUMMARY
Genetic and cell biology studies have identified endosomal trafficking as a key cytopathological pathway
in both Down Syndrome (DS) and Alzheimer’s disease (AD). However, biomarkers reflecting endosomal traffic
defects are still lacking. Current neuroimaging and cerebrospinal fluid (CSF) biomarkers assessed in individuals
with DS primarily focus on the histopathology of AD—that is, biomarkers linked to neurofibrillary tangles and
amyloid plaques. This proposal is thus designed to expand this focus to develop and validate new biomarkers of
the ‘cell biology’ of AD in DS, focusing on endosomal dysfunction, the earliest neuropathological alteration yet to
be identified in individuals with DS, preceding amyloid plaques and tau pathology. Such biomarkers would have
the potential to accelerate drug discovery, as therapeutic interventions currently being developed for the general
population, targeting the AD endosomal trafficking pathway, could also greatly benefit the DS population.
In a recent effort to identify new biomarkers for the endosomal trafficking defects in AD, and potentially
AD in people with DS, we performed a CSF proteomic screen of a conditional knock out (KO) mouse showing
endosomal trafficking defects, in which the VPS35 protein was selectively depleted in forebrain neurons. Among
the proteins found elevated in the CSF of VPS35 KO mice relative to control littermates were well established n-
terminal fragments of BACE1 substrates including, Amyloid Precursor Protein (APP); Amyloid Beta Precursor
Like Proteins 1 and 2 (APLP1 and APLP2); and Neural cell adhesion molecule L1-like protein (CHL1). Two of
these protein fragments -- n-APLP1 and n-CHL1-- were further validated in human CSF from cognitively healthy
participants and patients with prodromal AD. Collectively, our mouse-to-human studies suggest BACE1
substrates as potential biomarkers of endosomal dysfunction, a cytopathological characteristic of early stages of
AD. Relying on these exciting findings, and since endosomal abnormalities are detected in people with DS
decades before any classical AD neuropathology develops, we hypothesize that these endosomal biomarker
candidates can also hold potential as biomarkers for the early detection of AD in individuals with DS.
The overarching goal of this proposal is thus to focus on one of these candidates – n-APLP1 –
and to investigate its potential as an early biomarker of endosomal dysfunction for AD. Completion of
this study will provide initial evidence that n-APLP1 can act as the earliest biomarker for the detection
and tracking of AD progression in people with DS. Moreover, development of such biomarker would
support future therapeutic trials specifically designed to prevent and treat endosomal trafficking
dysfunction in AD that could benefit the DS population.

Grant Number: 1R21AG083593-01
NIH Institute/Center: NIH
Principal Investigator: Sabrina Alves Simoes Spassov