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Designed macrocyclic peptide rescues behavioral impairment and brain pathology in an Alzheimer’s disease mouse model

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-β (Aβ) plaques, with currently limited therapeutic options. We explored the potential of a macrocyclic peptide, 2E, designed to robustly inhibit Aβ self-aggregation by mimicking the interaction surface of islet amyloid polypeptide (IAPP) with Aβ. Our findings from two treatment paradigms in 5XFAD female and male mice revealed a significant reduction in cortical amyloid deposition, decreased neuronal damage, and enhanced astrocytic activation upon 2E administration. Furthermore, treated mice displayed improvements in memory and motor functions without any alterations in anxiety or stress responses, as evidenced by behavioral tests. Notably, RNA-seq analyses highlighted 2E's ability to bolster astrocytic activation while reversing AD-associated neuronal gene expression changes. Importantly, following intraperitoneal injection, 2E's presence in the brain attests to its biodistribution capability. Thus, the macrocyclic peptide 2E, either as a standalone or combined with other anti-amyloid strategies, emerges as a promising candidate to combat Aβ-driven AD pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE246244 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer’s disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD. Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and hypertrophic reactive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Ab aggregates in the brain of APP/PS1 mice An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.

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Designed macrocyclic peptide rescues behavioral impairment and brain pathology in an Alzheimer’s disease mouse model

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