Alzheimer's disease (AD), the most common type of dementia in the elderly, is a chronic and progressive neurodegenerative disorder with no effective disease-modifying treatments to date. Studies have shown that an imbalance in brain metal ions, such as zinc, copper, and iron, is closely related to the onset and progression of AD. Many efforts have been made to understand metal-related mechanisms and therapeutic strategies for AD. Emerging evidence suggests that interactions of brain metal ions and apolipoprotein E (ApoE), which is the strongest genetic risk factor for late-onset AD, may be one of the mechanisms for neurodegeneration. Here, we summarize the key points regarding how metal ions and ApoE contribute to the pathogenesis of AD. We further describe the interactions between metal ions and ApoE in the brain and propose that their interactions play an important role in neuropathological alterations and cognitive decline in AD.

Copper (Cu) has been implicated in the progression of Alzheimer’s disease (AD), and aggregation of Cu and amyloid β peptide (Aβ) are considered key pathological features of AD. Metal chelators are considered to be potential therapeutic agents for AD because of their capacity to reduce metal ion-induced Aβ aggregation through the regulation of metal ion distribution. Here, we used phage display technology to screen, synthesize, and evaluate a novel Cu(II)-binding peptide that specifically blocked Cu-triggered Aβ aggregation. The Cu(II)-binding peptide (S-A-Q-I-A-P-H, PCu) identified from the phage display heptapeptide library was used to explore the mechanism of PCu inhibition of Cu²⁺-mediated Aβ aggregation and Aβ production. In vitro experiments revealed that PCu directly inhibited Cu²⁺-mediated Aβ aggregation and regulated copper levels to reduce biological toxicity. Furthermore, PCu reduced the production of Aβ by inhibiting Cu²⁺-induced BACE1 expression and improving Cu(II)-mediated cell oxidative damage. Cell culture experiments further demonstrated that PCu had relatively low toxicity. This Cu(II)-binding peptide that we have identified using phage display technology provides a potential therapeutic approach to prevent or treat AD.

Parkinson’s disease (PD) is characterized by the presence of Lewy bodies caused by α-synuclein. The imbalance of zinc homeostasis is a major cause of PD, promoting α-synuclein accumulation. ATP13A2, a transporter found in acidic vesicles, plays an important role in Zn²⁺ homeostasis and is highly expressed in Lewy bodies in PD-surviving neurons. ATP13A2 is involved in the transport of zinc ions in lysosomes and exosomes and inhibits the aggregation of α-synuclein. However, the potential mechanism underlying the regulation of zinc homeostasis and α-synuclein accumulation by ATP13A2 remains unexplored. We used α-synuclein-GFP transgenic mice and HEK293 α-synuclein-DsRed cell line as models. The spatial exploration behavior of mice was significantly reduced, and phosphorylation levels of α-synuclein increased upon high Zn²⁺ treatment. High Zn²⁺ also inhibited the autophagy pathway by reducing LAMP2a levels and changing the expression of LC3 and P62, by reducing mitochondrial membrane potential and increasing the expression of cytochrom C, and by activating the ERK/P38 apoptosis signaling pathway, ultimately leading to increased caspase 3 levels. These protein changes were reversed after ATP13A2 overexpression, whereas ATP13A2 knockout exacerbated α-synuclein phosphorylation levels. These results suggest that ATP13A2 may have a protective effect on Zn²⁺-induced abnormal aggregation of α-synuclein, lysosomal dysfunction, and apoptosis.

Hydrogen peroxide (H₂O₂)-induced neuronal apoptosis is critical to the pathology of Alzheimer’s disease (AD) as well as other neurodegenerative diseases. The neuroprotective effects of apolipoprotein (ApoE) isoforms against apoptosis and the underlying mechanism remains controversial. Here, we have generated human cortical neurons from iPSCs and induced apoptosis with H₂O₂. We show that ApoE2 and ApoE3 pretreatments significantly attenuate neuronal apoptosis, whereas ApoE4 has no neuroprotective effect and higher concentrations of ApoE4 even display toxic effect. We further identify that ApoE2 and ApoE3 regulate Akt/FoxO3a/Bim signaling pathway in the presence of H₂O₂. We propose that ApoE alleviates H₂O₂-induced apoptosis in human iPSC-derived neuronal culture in an isoform specific manner. Our results provide an alternative mechanistic explanation on how ApoE isoforms influence the risk of AD onset as well as a promising therapeutic target for diseases involving neuronal apoptosis in the central nervous system.

Alzheimer’s disease (AD) is the most common cause of dementia, emphasizing the critical need for the development of biomarkers that facilitate accurate and objective assessment of disease progression for early detection and intervention to delay its onset. In our study, three AD datasets from the Gene Expression Omnibus (GEO) database were integrated for differential expression analysis, followed by a weighted gene co-expression network analysis (WGCNA), and potential AD biomarkers were screened. Our study identified UBE2N as a promising biomarker for AD. Functional enrichment analysis revealed that UBE2N is associated with synaptic vesicle cycling and T cell/B cell receptor signaling pathways. Notably, UBE2N expression levels were found to be significantly reduced in the cortex and hippocampus of the Tau^P301S mice. Furthermore, analysis of single-cell data from AD patients demonstrated the association of UBE2N and T cell function. These findings underscore the potential of UBE2N as a valuable biomarker for AD, offering important insights for diagnosis and targeted therapeutic strategies.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to progressive cognitive decline. With the development of machine learning analysis, screening biomarkers based on existing clinical data is becoming conducive to understanding the pathogenesis of AD and discovering new treatment targets. Our study integrated three AD datasets in the GEO database for differential expression analysis. After constructing a WGCNA network, 109 key genes were obtained and 48 core genes were analyzed from 109 genes using a protein-protein interaction network. The least absolute shrinkage and selection operator, support vector machine recursive feature elimination, and Random Forest methods were applied to obtain the features associated with the 48 core genes and 13 potentially related AD biomarkers were selected. By intersecting InnateDB database with them, we found a potential immune-related marker, UBE2N. MFUZZ cluster analysis revealed that UBE2N is closely related to T cell and B cell functions and the synaptic vesicle cycle signaling pathways. In addition, the expression levels of UBE2N were decreased in the temporal cortex and hippocampus of Tau^P301S mice but not APP/PS1 mice. Our findings are the first comprehensive identification of UBE2N as a biomarker for AD, paving the way for much-needed early diagnosis and targeted treatment.