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PARP16-Mediated Stabilization of Amyloid Precursor Protein mRNA Exacerbates Alzheimer's Disease Pathogenesis

Jinghuan Wang¹, Qianwen Cheng¹, Yuyu Zhang¹

¹Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai 201203, China.

Aging and Disease

|May 10, 2023

Abstract:

The accumulation and deposition of beta-amyloid (Aβ) are key neuropathological hallmarks of Alzheimer's disease (AD). PARP16, a Poly(ADP-ribose) polymerase, is a known tail-anchored endoplasmic reticulum (ER) transmembrane protein that transduces ER stress during pathological processes. Here, we found that PARP16 was significantly increased in the hippocampi and cortices of APPswe/PS1dE9 (APP/PS1) mice and hippocampal neuronal HT22 cells exposed to Aβ, suggesting a positive correlation between the progression of AD pathology and the overexpression of PARP16. To define the effect of PARP16 on AD progression, adeno-associated virus mediated-PARP16 knockdown was used in APP/PS1 mice to investigate the role of PARP16 in spatial memory, amyloid burden, and neuroinflammation. Knockdown of PARP16 partly attenuated impaired spatial memory, as indicated by the Morris water maze test, and decreased amyloid deposition, neuronal apoptosis, and the production of inflammatory cytokines in the brains of APP/PS1 mice. In vitro experiments demonstrated that the knockdown of PARP16 expression rescued neuronal damage and ER stress triggered by Aβ. Furthermore, we discovered that intracellular PARP16 acts as an RNA-binding protein that regulates the mRNA stability of amyloid precursor protein (APP) and protects targeted APP from degradation, thereby increasing APP levels and AD pathology. Our findings revealed an unanticipated role of PARP16 in the pathogenesis of AD, and at least in part, its association with increased APP mRNA stability.

Insights

Poly(ADP-ribose) polymerase 16 (PARP16) overexpression correlates with Alzheimer's disease (AD) progression. Reducing PARP16 improved memory, decreased amyloid plaques, and lessened neuroinflammation in AD mouse models.

Area of Science:

Neuroscience
Molecular Biology
Pathology

Background:

Alzheimer's disease (AD) is characterized by beta-amyloid (Aβ) accumulation.
PARP16, a Poly(ADP-ribose) polymerase, is an ER transmembrane protein involved in ER stress.
PARP16 levels are elevated in AD models, suggesting a role in disease progression.

Purpose of the Study:

To investigate the role of PARP16 in Alzheimer's disease pathogenesis.
To determine the effect of PARP16 on cognitive function, amyloid burden, and neuroinflammation in AD.

Main Methods:

Utilized APPswe/PS1dE9 (APP/PS1) mice and HT22 cells exposed to Aβ.
Employed adeno-associated virus (AAV)-mediated PARP16 knockdown in APP/PS1 mice.
Assessed spatial memory using the Morris water maze test.
Analyzed amyloid deposition, neuronal apoptosis, and inflammatory cytokine production.
Conducted in vitro experiments to evaluate neuronal damage and ER stress.

Main Results:

PARP16 expression was significantly increased in AD mouse brains and Aβ-treated cells.
PARP16 knockdown in APP/PS1 mice partially rescued spatial memory deficits.
Reduced amyloid deposition, neuronal apoptosis, and neuroinflammation were observed following PARP16 knockdown.
In vitro, PARP16 knockdown mitigated Aβ-induced neuronal damage and ER stress.
PARP16 was identified as an RNA-binding protein that enhances amyloid precursor protein (APP) mRNA stability.

Conclusions:

PARP16 plays a significant, previously unrecognized role in Alzheimer's disease pathogenesis.
PARP16 contributes to AD pathology by increasing APP mRNA stability and subsequent APP levels.
Targeting PARP16 may offer a therapeutic strategy for Alzheimer's disease.

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