# "A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways"

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $973,393

## Abstract

PROJECT SUMMARY
 Alzheimer’s Disease (AD) is the most common form of dementia, characterized by misfolding and
aggregation of specific proteins which manifest in pathological features including neuronal loss, cognitive decline
and histopathological hallmarks such as the accumulation of amyloid plaques and neurofibrillary tangles in the
brain. Amyloid plaques comprise extracellular deposits of amyloid-b (Ab) aggregates, where Aβ oligomers are
thought to be proteotoxic to neuronal function. Numerous studies have demonstrated that AD-associated
proteotoxicity triggers an adaptive unfolded protein response (UPR) which attempts to restore proteostatic
dysfunction due to accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR signaling is
mediated through PERK/eIF2a, IRE1/XBP1, and ATF6 sensor pathways; relative contributions of these signaling
arms to neurodegeneration is complex as they have dual roles in mediating cell survival and cell death.
Elevations in PERK/phosphorylated eIF2a, XBP1 mRNA splicing, and increased levels of ER chaperones such
as BiP/GRP78, GRP94 and PDI in human AD brain strongly suggests chronic activation of ER stress is evident
in human AD pathology. Further, a polymorphism previously linked to bipolar disorders within the XBP1 promoter
region was linked to increased AD risk in Chinese populations. Although it has been established that UPR
pathways are activated in disorders such as AD, it is not clear whether UPR pathways confer neuroprotective
effects, or if their activation can contribute to pathogenesis.
 Potential neuroprotective effects of the ATF6 pathway in neurodegeneration have remained particularly
elusive. ATF6 functions as an ER stress sensor and transcription factor that promotes expression of genes that
enhance proper protein folding via increased production of ER chaperones and increased degradation of
misfolded proteins. We present new evidence that ATF6 is essential for synaptic function, as Atf6-/- mice display
cognitive and behavioral defects associated with reduced synaptic spine density. Further, exogenous expression
of the active ATF6 form suppressed accumulation of amyloid fibrils in a murine model of AD. These results
provide strong evidence that ATF6 activation may have a physiological role in synaptic activity and cognitive
behavior, and acute ATF6 activation can confer neuroprotective effects with AD-associated proteotoxicity. In the
proposed study, our efforts will be focused on elucidating potential neuroprotective effects of ATF6 on neuronal
and synaptic function, and differentiate potential roles for ATF6 in neurons and microglia. Given the effects of
ATF6 on attenuating Aβ plaque formation, we will characterize proteins that are particularly susceptible to
proteostatic dysfunction in AD. We will also characterize the effects of ATF6 mutational variants identified in
human Achromatopsia patients on neuronal function, and determine whether pharmacological activation of ATF6
is p...

## Key facts

- **NIH application ID:** 9878055
- **Project number:** 5R01AG062190-02
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Timothy Yikai Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $973,393
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878055

## Citation

> US National Institutes of Health, RePORTER application 9878055, "A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways" (5R01AG062190-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878055. Licensed CC0.

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