Background: Alzheimer’s disease (AD) is characterized by neuroinflammation, which is frequently accompanied by immune system dysfunction. Although the mechanism of neurodegenerative lesions is unclear, various clinical trials have highlighted that early intervention in AD is crucial to the success of treatment. In order to explore the potential of immunotherapy in the early period of AD, the present study evaluated whether application of glatiramer acetate (GA), an immunomodulatory agent approved for remitting–relapsing multiple sclerosis (RRMS), in the early stages of AD prior to amyloid beta (Aβ) deposition altered the Aβ pathology and cognitive impairments in APPswe/PSEN1dE9 (APP/PS1) transgenic mice.Methods: We treated two cohorts of pre-depositing and amyloid-depositing (2- and 6-month-old) APP/PS1 mice with weekly-GA subcutaneous injection over a 12-week period. We then tested spatial learning and memory using the Morris water maze (MWM) and the Y maze. Immunohistochemistry staining was utilized to analyze Aβ burden in the brain as well as activated microglia. Furthermore, the inflammatory cytokine milieu within brains was estimated by quantitative real-time polymerase chain reaction, and the peripheral CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) in the spleen were measured by flow cytometry.Results: We found that early GA administration reduced Aβ burden and ameliorated cognitive decline. Meanwhile, the immune microenvironment had changed in the brain, with an increase in the production of anti-inflammatory cytokines and a decrease in microglial activation. Interestingly, early GA administration also modulated the peripheral immune system through the amplification of Tregs in the spleen.Conclusion: Overall, our findings revealed that GA treatment might enhance the central and peripheral immune systems’ protective capabilities in the early stages of AD, eventually improving cognitive deficits. Our research supports the advantages of immunomodulatory treatments for AD at an early stage.

The massive cell death of dopaminergic neurons (DANs) in substantia nigra pars compacta (SNC) is associated with motor diseases, such as Parkinson’s disease. Moreover, as a subtype of DANs in SNC, ALDH1A1⁺ neurons show better resistance to PD related neurotoxin. DANs can also be found in the substantia nigra pars reticulata (SNR), however, whether they are ALDH1A1⁺ neurons are rarely reported, as well as their projection, function, and reaction in the PD pathology. We studied the distribution of ALDH1A1⁺ neurons and track their projection by injecting pAAV. We figured out that, in SNR, 87 % neurons are ALDH1A1⁺/TH⁺ in ALDH1A1⁺ cluster averagely, while ALDH1A1⁺/TH⁺: TH⁺ is 52 % averagely. There are two enrichment regions of ALDH1A1⁺/TH⁺ neurons at brgma −3.40 mm and brgma −3.70 mm in the SNR of the nTg mice. Nevertheless, in one type of PD-liked mice model, the proportion of ALDH1A1⁺/TH⁺: ALDH1A1⁺ neurons are 98 % averagely, while ALHD1A1⁺/TH⁺: TH⁺ is 57 %. Intriguingly, neuro-tracing discovered that there may be a previously unreported connection between SNR and anterior dorsal thalamus (ADT). The mouse received MPTP stereotactic injection to destroy TH⁺ neurons in SNR showed depression behavior, indicated the DANs death in SNR may contribute to depression behavior.

Parkinson’s disease (PD) is the world’s second most prevalent neurodegenerative disease. Currently, aside from levodopa, there are no other effective drugs clinically available to slow its progression. Otx2 plays a critical role in the differentiation of midbrain dopaminergic neurons (mDANs) during midbrain development. However, in adulthood, Otx2 is primarily expressed in the ventral tegmental area (VTA)-ventral part, and mDANs in the dorsal part of the VTA and the substantia nigra pars compacta (SNc) show no Otx2 expression. Research indicates that Otx2 is essential not only for the development of mDANs but also for their protection against the toxicity of MPTP and rotenone. Consequently, Otx2 is a potential clinical target for mDANs protection. Identifying the upstream mechanism that regulates Otx2 expression is crucial to restoring its expression in the SNc and enhancing its levels in the entire ventral midbrain mDANs. In this study, we have demonstrated the safety of Otx2 overexpression in vitro using adeno-associate virus (AAV) and explored the feasibility of promoting Otx2 expression through the Wnt/β-Catenin signaling pathway using various drugs, a miR-34 mimic, and an inhibitor. Our results showed that Otx2 overexpression via AAV in the SNc is relatively safe, and CHIR99021 can induce Otx2 expression in mouse mDANs, thereby, alleviating PD-liked motor symptoms induced by MPTP. These findings suggest that modulating Otx2 expression through the Wnt/β-Catenin signaling pathway holds a therapeutic approach for Parkinson’s disease.