Exploring the link between GBA1 mutations and Dementia with Lewy bodies, A mini-review.

IMPORTANCE: Dementia with Lewy bodies (DLB) is a neurodegenerative disease linked to abnormal accumulation of phosphorylated α-synuclein. GBA1 is the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), whose mutations are a risk factor of DLB. OBJECTIVE: To report all available data exploring the association between GBA1 mutations and DLB. EVIDENCE REVIEW: All publications focused on GCase and DLB in humans between 2003 and 2022 were identified on PubMed, Cochrane and ClinicalTrials.gov. FINDINGS: 29 studies were included and confirmed the strong association between GBA1 mutations and DLB (Odds Ratio [OR]: 8.28). GBA1 mutation carriers presented a more malignant phenotype, with earlier symptom onset, more severe motor and cognitive dysfunctions, more visual hallucinations and rapid eye movement sleep disorder. GBA1 mutations were associated with "purer" neuropathological DLB. No therapeutic recommendations exist and clinical trials targeting GCase are just starting in DLB patients. CONCLUSIONS AND RELEVANCE: This review reports a link between GBA1 mutations and the DLB phenotype with limited evidence due to the small number of studies.

STAT3 inhibition protects against neuroinflammation and BACE1 upregulation induced by systemic inflammation.

Abnormal activation of the transcriptional factor STAT3 (signal transducer and activator of transcription 3) was recently associated with Alzheimer Disease (AD). STAT3 phosphorylation is critical for cytokine secretion linked to neuroinflammation. Moreover, STAT3 may act as a transcriptional regulator of BACE1 (ß-APP cleaving enzyme-1), the key enzyme in amyloid ß (Aß) production. We have previously shown that neuroinflammation and increased brain BACE1 levels triggered by LPS-induced systemic inflammation in wild-type mice are associated with an enhanced STAT3 activation. Using this LPS model, the goal of this study was to investigate if a STAT3 inhibitor administration could be protective against neuroinflammation and abnormal BACE1 regulation. Our results show that intraperitoneal injection of Stattic, a molecule that selectively inhibits the activation of STAT3, decreases LPS-induced microglial activation in the hippocampus. In addition, STAT3 inhibition reduced brain levels of cytokines IL-6, IL-1ß and TNF-α triggered by LPS systemic administration. A significant reduction of BACE1 levels was observed in the hippocampus of mice treated with LPS and Stattic compared to those exposed to LPS alone. Taking together, our results show that Stattic can protect hippocampus against two pathological hallmarks of AD, and pave the way for further explorations of the therapeutic potential of STAT3 inhibition in AD.