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.