# Causes and consequences of differential APP processing in inhibitory and excitatory neurons

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $713,402

## Abstract

SUMMARY
Alzheimer's disease (AD) was once considered a monolithic disorder of canonical symptoms and definitive
pathology, but recent work has identified considerably heterogeneity in onset, progression, and histologic
features. Despite this important shift in clinical perspective, we don't yet know if or how the range of brain
pathologies explains the diversity in clinical trajectories. We also can't explain how neuropathological diversity
arises in the first place, even for the canonical traits of amyloid, tangles, and neurodegeneration. It would be
instructive to understand how such diverse structures arise and what if any role each plays in cognitive decline,
but this insight has been stymied by human pathological heterogeneity combined with a paucity of appropriate
animal models to replicate these extremes. We unexpectedly discovered a possible cellular explanation for the
emergence of neuritic vs diffuse amyloid structures while characterizing two new transgenic lines that
expressed the same APP construct selectively in glutamatergic or GABAergic neurons. Both models
developed pronounced Ab deposits, but showed divergent patterns of pathology and Ab profiles.
Glutamatergic APP mice formed cored, thioflavin-positive neuritic plaques composed of both Ab40 and 42,
while GABAergic APP mice formed diffuse, thioflavin-negative plaques composed primarily of Ab42. These
complementary APP transgenic models, with their respective diffuse and neuritic plaque pathology, now allow
us to directly test the role of neuronal subtypes in plaque heterogeneity, identify the mechanistic basis for these
differences in APP processing, and determine how distinct plaque structures may be pathogenic or protective
through the divergent response of neighboring cells. Aim 1 will characterize the physical differences that
distinguish plaques generated by GABAergic vs glutamatergic neurons using electron microscopy, in vivo
seeding assays, and mass spectrometry. Aim 2 will determine how neuron-specific differences in APP
processing arise using snRNAseq transcriptomic analysis of each neuronal subtype. This aim will also
ascertain whether APP processing differences extend from overexpressed pathogenic APP to wild-type protein
expressed at endogenous levels. Finally, Aim 3 will dissect the downstream consequences of each aggregate
structure at the cell/molecular level using snRNAseq data and by testing cognitive function. Collectively we
expect these studies may cast a new light on excitatory:inhibitory balance in AD and advance a new
appreciation of neuronal heterogeneity as an important facet of disease pathogenesis.

## Key facts

- **NIH application ID:** 10823748
- **Project number:** 1R01AG085751-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** JOANNA L JANKOWSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $713,402
- **Award type:** 1
- **Project period:** 2024-05-15 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823748

## Citation

> US National Institutes of Health, RePORTER application 10823748, Causes and consequences of differential APP processing in inhibitory and excitatory neurons (1R01AG085751-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10823748. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*