Myelin is formed by oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system. The myelin sheath is a layer of fat and protein that covers the axon of a nerve cell, enabling the electrical impulses between nerve cells to travel back and forth rapidly [22]. Myelin is essential for healthy brain functioning, and myelin wraps around axons to increase neural signaling speed, enabling complex neuronal mechanisms underlying learning and cognition [23]. There is growing evidence that myelin disruption is an important factor contributing to the age-related loss of brain plasticity and repair responses [24]. There is close agreement between neuropsychology, neuropathology, and imaging measures suggesting that the process of myelin breakdown begins in adulthood, accelerates with human aging, and underlies age-related cognitive declines, and the most potent risk factor of dementia-causing disorders, such as AD, is age [25]. In vivo AD models have shown that alterations of myelin morphology and oligodendrocyte development appear before the formation of amyloid and tau pathologies. However, these alterations might be highly associated with different mutations in the AD models [26]. It has been reported that oligodendrocytes were more vulnerable to stressors in the presence of AD-associated presenilin-1 (PS1) mutations and in embryonic neurons, amyloid precursor protein (APP) mutations may interfere with myelination via axon-mediated signaling to oligodendrocytes in 3xTg-AD models while others do not so [27, 28].

Amyloid $\beta$-peptide plaques have been confirmed to be the pathological hallmark of AD, and multiple lines of evidence have linked A$\beta$ with AD-associated neuronal degeneration. Numerous studies have proposed that A$\beta$ alters myelinating oligodendrocyte functions and induces toxicity in AD [29].

The direct toxicity generated by pathological A$\beta$ peptides alone or combined with the signals produced by degenerating neurons leads to oligodendrocytes compromise, which participates in the disease process [30]. The response of OPCs to A$\beta$, such as demyelination, increased proliferation, reactive microglia triggering, and default response to any brain injury, is described in several studies [31]. Furthermore, in the initial phase of AD, the reactions of OPCs to the increased differentiation of oligodendrocytes are also described. The myelin disruption induced by A$\beta$-mediated toxicity is associated with the spatial and temporal progress of cognitive disorder in the AD model in vivo during the early pre-symptomatic stages [32]. As shown in some in vitro studies, a new pathogenic mechanism underlying oligomer-mediated leukopenia degeneration may impair myelin maintenance and regeneration of adult OPCs, consequently leading to cumulative damage to myelin axons and to nerve disconnection [33]. Oligodendrocyte precursor cells, potential sources for myelin defect repair, have different outcomes in AD-associated mouse models and human AD pathology because of their specific response to amyloid plaque deposition [25]. AD-associated presenilin-1 mutations increase A$\beta$-induced myelin damage and oligodendrocyte dysfunction in the pre-symptomatic phase of early AD [34]. Here, we show that the PS1 mutation made mouse OPCs vulnerable to A$\beta$-induced cell differentiation. In addition, PS1 expression is closely related to OPC function and the distribution of myelin basic protein (MBP), a process further exacerbated by the exposure to A$\beta$ [35]. Furthermore, demyelination was observed where the A$\beta$ plaques were the most abundant. In preclinical and sporadic AD cases, focal loss of oligodendrocytes in neocortical gray matter was relevant to the core of A$\beta$ plaques [36]. As demonstrated in immunoreactive research, high levels of A$\beta$ tend to be positively correlated with marker expression in oligodendrocytes (there are three types of myelin basic proteolipid protein: galactocerebroside, myelin glycoprotein, and myelin/oligodendrocyte glycoprotein), implicating that A$\beta$ plaque formation may be preceded by neuronal/oligodendrocytic degeneration [37]. However, contradictory literature indicates that oligodendrocyte survival, myelination, and OPCs seem to be affected by A$\beta$ [38]. Acute inflammation induced by A$\beta$ enhanced remyelination-related transcription signals and rapidly cleared myelin debris. Along with the visibly distinct outcomes between an AD-related mouse model and human AD pathology, APP/PS1 mice had a greater number of oligodendrocyte lineage cells, and a decrease in oligodendrocyte number was found in the postmortem human cortex of patients with AD [34, 39]. In addition, defects in myelin integrity and amount were prevalent in APP/PS1 mice at six months of age but were normalized in control mice at nine months [40]. There is a possibility of repair from newly formed oligodendrocytes in APP/PS1 mice, but in human AD, this response from oligodendrocyte progenitors does not seem as evident.

Neurofibrillary tangles, known as pathological hallmarks of AD, are intracellular aggregates of hyperphosphorylated tau protein known as microtubule-associated proteins. Brains affected by AD are also commonly affected by NFTs, especially in the hippocampus and entorhinal cortex [41]. A hippocampus and temporal cortex with NFTs can also be observed in normal elderly individuals and patients suffering from other neurodegenerative diseases [42]. Clinical symptom severity and the degree of neuronal death increase the number of NFTs with aging.

Tau hyperphosphorylation and accumulation frequently occur in neurons but were also found in non-neuronal glial cells [43]. Mice with the G272V mutation (mutations in tau) developed oligodendroglial fibrillary lesions similar to those seen in human tauopathies [44]. In oligodendrocyte cytoplasm, tau-positive fibrillary tangles resemble NFTs in terms of argyrophilia and antigenicity to tau and ubiquitin [45]. Despite this, the role of oligodendrocytes in NFT formation is still not fully understood. This suggests that oligodendrocyte dysfunction and NFTs share a similar background in that axonal dysfunction can neither transmit nor conduct electrical signals using myelin [46]. However, the specific causality between oligodendrocyte dysfunction and NFTs remains unclear.

Inflammation and oxidative stress are common pathophysiological factors that cause oligodendrocyte dysfunction and NFT formation in AD. According to some researchers, inflammation and oxidative stress induced by NFTs may contribute to oligodendrocyte dysfunction [47]. Therefore, it is important to investigate whether oligodendrocyte dysfunction is either a cause or a consequence of NFTs in AD. The exact role that oligodendrocytes play in NFT pathogenesis remains unknown.

The overlap of transcriptomic features between DOL and DAA suggests that despite fundamental differences between functions of astrocytes and oligodendrocytes, they share similar damage response molecular pathways (Serpina3n, C4b, and Ctsb upregulation). Microglial responses appear to be more pathologically specific, such as disease-associated microglia (DAM) observed in amyloidosis, but not in tau pathology [60]. Notably, some genes, such as C4b, are also found as common features of both astrocytes and oligodendrocytes [61]. Therefore, further studies are needed to determine the role of these responses and their targeting in the development of effective treatments for CNS diseases.

Interestingly, SERPINA3+ oligodendrocytes in human postmortem AD brains were observed using immunohistochemistry [62]. Transcriptomics results have revealed that a high level of SERPINA3 signature in proximity to macrophages is associated with inflammation, suggesting that neuroinflammation and damage can potentially induce increased expression of SERPINA3 [63]. However, the presence of only a single marker in the immunohistochemistry may not be sufficient to determine the degree of similarity between these cells and mouse DOLs. Furthermore, spatial transcriptomics could not fully characterize this marker and it lacked single cell resolution. Notably, it was found that the proportion of SERPINA3+ cells in the brain has been associated with Mini-Mental State Examination (MMSE) scores, suggesting SERPINA3 may be an indicator of impaired cognitive function. A notable effect of Serpina3n is that it inhibits granzyme B, thereby protecting cells against CD8+ T-cell-induced cytotoxicity [64]. Furthermore, it promoted plaque aggregation in vitro [65]. Further research is required to better understand the role of DOLs, particularly Serpina3n/SERPINA3, and their relevance to human diseases.

In experimental allergic encephalomyelitis (EAE), oligodendrocyte progenitors (OPC) and mature oligodendrocytes with similar characteristics are phagocytic, present antigens on MHC-II, and stimulate CD4+ T cells [66]. Unlike EAE, scRNA-seq analysis of the transcriptomic profile of mature oligodendrocytes (GalC+) in 5xFAD revealed upregulation of the MHC-I pathway but not of the MHC-II pathway. Therefore, CD8+ T cells are more likely to interact with the immune system than CD4+ T cells. In addition, a recent study suggests that OPC may age in the presence of amyloidosis [67]. The authors have not found any evidence of senescence markers at the transcriptome level in mature oligodendrocytes. However, a more in-depth description of OPC is needed to answer these questions. Consistent with observations in the 5xFAD model, the expression levels of DOL genes in EAE were found to increase with disease progression, supporting the idea that DOL signaling expression and damage accumulation are related.