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Abstract Background 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. Methods 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). Results 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 GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ 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. Conclusions 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.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is frequently found in athletes and those who have experienced repetitive head traumas. CTE is associated with a variety of neuropathologies, which cause cognitive and behavioral impairments in CTE patients. However, currently, CTE can only be diagnosed after death via brain autopsy, and it is challenging to distinguish it from other neurodegenerative diseases with similar clinical features. To better understand this multifaceted disease and identify metabolic differences in the postmortem brain tissues of CTE patients and control subjects, we performed ultra-high performance liquid chromatography–mass spectrometry (UPLC-MS)-based non-targeted metabolomics. Through multivariate and pathway analysis, we found that the brains of CTE patients had significant changes in the metabolites involved in astrocyte activation, phenylalanine, and tyrosine metabolism. The unique metabolic characteristics of CTE identified in this study were associated with cognitive dysfunction, amyloid-beta deposition, and neuroinflammation. Altogether, this study provided new insights into the pathogenesis of CTE and suggested appealing targets for both diagnosis and treatment for the disease.

Traumatic brain injury (TBI) leads to long-term cognitive impairments, with an increased risk for neurodegenerative and psychiatric disorders. Among these various impairments, olfactory dysfunction is one of the most common symptoms in TBI patients. However, there are very few studies that show the association between olfactory dysfunction and repetitive TBI. To investigate the effects of repetitive TBI on olfactory functioning and the related pathological neuronal injuries in mice, we applied a weight-drop model of TBI and performed neuropathological examinations and electroencephalography (EEG) in olfactory-bulb-associated areas. Through neuropathological examinations, we found significant increases of amyloid precursor protein (APP) and phosphorylated Tau (p-Tau) (S202/T205) in olfactory-bulb-associated areas. Neuronal atrophy in the lateral anterior olfactory nucleus (AOL), granule layer olfactory bulb (GrO), and dorsal tenia tecta (DTT) was also found to be correlated with p-Tau levels. However, there was no difference in the total Tau levels in the olfactory-bulb-associated areas of TBI mice. Electroencephalography (EEG) of repetitive TBI mouse models showed impaired spontaneous delta oscillation, as well as altered cross-frequency coupling between delta phase and amplitudes of the fast oscillations in the resting-state olfactory bulb. Furthermore, abnormal alterations in EEG band powers were observed during the olfactory oddball paradigm test. TBI also led to impairments of the olfactory-function-associated behaviors. This study provides evidence of behavioral, neuropathological, and physiological alterations in the mouse olfactory system caused by repetitive TBI. Together, p-Tau alterations and EEG impairments may serve as important biomarkers of olfactory-track-associated dysfunctions in repetitive TBI.