4.1. T cells in Alzheimer’s disease
AD is the most prevalent neurodegenerative disorder among elderly adults, often progressing to dementia. It primarily manifests as cognitive impairments, including memory loss, language difficulties, misidentifications, and behavioral disturbances. These symptoms are linked to two protein changes in the brain. The first is hyperphosphorylation of the Tau protein, resulting in the formation of intracellular neurofibrillary tangles. The second is the formation of extracellular Aβ-peptide deposits, leading to the creation of amyloid plaques. Both of these processes result in synaptic loss and damage to neurons, contributing to the decline in cognitive function.
T cells, as fundamental cells in the adaptive immune system, may have different roles in the progression of the disease and either may contribute to the aggravation of the pathology or have a protective function in other cases (Table 2). Aberrant T cells may indirectly influence the pathogenesis of AD by secreting proinflammatory cytokines that maintain a detrimental neuroinflammatory state. However, the multifactorial role of T cells in the pathogenesis of AD is also related to an immune response to disease risk factors: the apolipoprotein E (APOE), Aβ peptide, secretases or Tau protein.
The APOE gene plays a significant role in AD by influencing the Tau neurotoxicity (Kang et al., 2021), and regulating the levels of Th17 and Treg cells. The specific allele of the APOE protein is crucial, as individuals with the APOE4 allele have higher levels of T cell activation and a higher risk of developing AD (Bonacina et al., 2018). As a result, this gene may be considered a potential target for controlling abnormal T cell activation in AD (Dai & Shen, 2021).
The presence of Aβ-reactive T cells is a result of APCs presenting either the Aβ precursor protein (APP) or Aβ peptide, cleaved by β- and γ-secretases. Both APP and exogenous Aβ can directly modulate T cell function. Additionally, expression of the precursor by monocytes triggers the release of proinflammatory cytokines, which indirectly activate T cells (Dai & Shen, 2021). The role of Aβ-reactive T cells remains controversial, as some animal studies have shown them to be beneficial in clearing Aβ peptides through IFNγ-mediated activation of microglia (Fisher, Nemirovsky, Baron & Monsonego, 2010), while others suggest that these T cells can strongly activate proinflammatory cytokines such as IL-6, TNFα and IL-1β, contributing to a neuroinflammatory and neurotoxic environment (Mietelska-Porowska & Wojda, 2017).
T cells have the ability to control the enzymes responsible for APP processing. T cell-mediated biological changes regulate the expression and activity of β-secretase, and in turn, influence T cell function. Furthermore, the Notch family of receptors are substrates of γ-secretase, which releases the Notch intracellular domain (NICD) during proteolysis for translocation to the nucleus and activation of transcription factors involved in T cell development (Dai & Shen, 2021). Additionally, α-secretase, which promote a non-amyloidogenic cleavage of APP, is also involved in T cell function by processing various substrates, while T cells promote α-secretase activation.
The presence of T cells in the brain is correlated with Tau pathology and can result in excessive T cell activation (Merlini, Kirabali, Kulic, Nitsch & Ferretti, 2018). In summary, T cells in AD may have a dual role. On the one hand, they can migrate into the CNS parenchyma and contribute to neuronal death during AD progression. However, T cell infiltration in the CNS parenchyma may also have a beneficial effect by promoting the restoration of glial function. In normal conditions, the T cell infiltrate in the CNS parenchyma has a neuroprotective role in spatial learning and preserving neurogenesis (Dai & Shen, 2021). Thus, it is important to thoroughly understand the immune response in AD in order to develop effective therapeutic strategies.