# Inflammation and plaque formation downstream of disrupted autophagy in Alzheimer's disease

> **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2024 · $87,267

## Abstract

Alzheimer’s disease and related dementias (AD/ADRD) are devastating diseases to those diagnosed and
come with a high cost to society. Reliable early identification and improved intervention is vital to treat patients
before neuronal loss is irreversible. Autophagy is strongly implicated in the progression of AD, and thus has
been an attractive therapeutic target for many years, but to reach a successful autophagy-targeting drug
requires better understanding of the molecular consequences of disrupted autophagy. I propose to investigate
how disrupted autophagy contributes to the chronic inflammation and plaque formation associated with the
progression of AD. Using two of the most common AD risk variants as models to disrupt specific aspects of
autophagy, I will investigate how the misregulation of mitochondrial DNA (mtDNA) and amyloid precursor
protein (APP), autophagy cargos I identified in my postdoc, contribute to neuroinflammation, synapse loss, and
plaque deposition observed in AD. AD initiation and progression involves multiple cell types, therefore I will use
innovative iPSC models and cutting-edge techniques to model and manipulate complex interactions between
neurons and microglia in a simplified system. In the K99 phase of this award, I will confirm that the ApoE4 AD
risk variant disrupts mitochondria-endoplasmic reticulum contacts, which I predict will impair the clearance of
mtDNA. I expect accumulation of mtDNA will sensitize neurons to release inflammatory factors, resulting in
sustained microglia activation, release of complement and synapse loss. In the R00 phase, I will apply similar
approaches mastered in the K99 phase to investigate the contribution of autophagy to plaque deposition. First,
based off preliminary data, I will determine whether APP is an autophagy cargo in neurons or microglia, and
whether it is normally transferred between the cell types. Second, as dysregulated Tau is a major disruptor of
microtubules and organelle trafficking, I will investigate the sensitivity of TauR317W neurons to disruptions to
autophagosome trafficking. I have found in my postdoctoral work that impaired autophagosome trafficking
decreases degradation and increases secretion of autophagy cargo, thus I expect TauR317W sensitizes neurons
to increase secretion and transfer of APP to microglia. I will then investigate the role of microglial autophagy to
prevent plaque formation, and how this may be perturbed by the accumulation of Tau aggregrates and
neurofibrillary tangles in TauR317W microglia. Completion of the independent aims will highlight the multifaceted
role of autophagy in disease progression, identify specific molecular consequences of disrupted autophagy,
and ultimately help to identify novel biomarkers and therapeutic targets for AD/ADRD.

## Key facts

- **NIH application ID:** 10904963
- **Project number:** 5K99NS133611-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Juliet Goldsmith
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $87,267
- **Award type:** 5
- **Project period:** 2023-08-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904963

## Citation

> US National Institutes of Health, RePORTER application 10904963, Inflammation and plaque formation downstream of disrupted autophagy in Alzheimer's disease (5K99NS133611-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10904963. Licensed CC0.

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