# SATB1 Exhibits a Protective Role in HAmylin‐Oligomer‐Induced Neuronal Damage and Cognition Decline

## TL;DR

This study shows that SATB1 protects neurons from damage caused by hAmylin oligomers, improving cognition and reducing neuronal death.

## Contribution

The novel role of SATB1 in protecting against hAmylin-induced neuronal damage via AKT3 activation is identified.

## Key findings

- SATB1 overexpression reduces hAmylin-induced mitochondrial dysfunction and neuronal apoptosis.
- SATB1 activates AKT3 transcriptionally to protect neurons from hAmylin damage.
- Knockdown of SATB1 worsens cognitive decline and neuronal damage in hAmylin-treated mice.

## Abstract

Amylin is a hormone secreted by pancreatic β cells, and oligomerized human amylin (hAmylin) has shown neurotoxicity in mice. However, the effect of hAmylin oligomers on cognitive ability and the underlying mechanisms remains unexplored.

In this study, hAmylin oligomers were bilaterally injected into the hippocampus of mice.

Inspiringly, hAmylin‐mice displayed obvious cognition decline and neuronal damages in the hippocampal dentate gyrus (DG) area. Thus, hippocampal tissues were collected for mRNA‐seq analysis, which identified the upregulation of transcription factor SATB Homeobox 1 (SATB1) in the hippocampus of hAmylin mice. Using behavioral experiments and histopathological analyses, the promoting effect of SATB1 knockdown on cognition decline and neuronal damage in hAmylin mice was determined. In vitro, SATB1 expression was reduced in primary hippocampus neurons after hAmylin oligomer incubation. SATB1 overexpression inhibited hAmylin‐induced mitochondrial dysfunction and neuronal apoptotic deaths, while SATB1 knockdown exhibited opposite effects. SATB1 transcriptionally activated AKT serine/threonine kinase 3 (AKT3) by binding to its promoter region, and AKT3 accounted for SATB1‐mediated protection against hAmylin‐induced mitochondrial dysfunction and neuronal injury.

In summary, this study highlights the novel role of SATB1 in hAmylin oligomer‐induced neuronal damage and cognition decline via AKT3.

In this study, bilateral hippocampal injections of hAmylin oligomers induced an obvious cognition decline in mice, along with upregulation of SATB1 in the mouse hippocampus. In hAmylin‐induced mice, SATB1 knockdown (KD) further aggravated the above changes. In hAmylin‐induced neurons, SATB1 KD promoted hAmylin–induced mitochondrial dysfunction and apoptosis, while SATB1 overexpression exhibited the opposite effect. Besides, SATB1 transcriptionally activated AKT3 to protect against these hAmylin‐induced disorders.