Page 41 - AN-3-1

Advanced Neurology Antibodies as neurodegenerative biomarkers

explored, although research in this field is less intense reactive antibodies directed against specific neuronal
than in AD. antigens such as myelin, which may influence the function
Recent findings suggest that antibodies are able not and viability of neurons, thereby contributing to their
83
only to inhibit pathological extracellular accumulation and degeneration (Table 2).
spreading 71,72 but also to identify and eliminate pathogenic Amyotrophic lateral sclerosis is characterized by
α-syn aggregates. Some antibodies can additionally the formation of abnormal protein aggregates, such as
73
reduce the damage and toxicity resulting from α-syn superoxide dismutase 1 (SOD1), fused in sarcoma (FUS),
oligomers by depleting the oligomers in the cytoplasm, and TAR DNA-binding protein 43 (TDP-43). Mutations
74
75
thereby mitigating their intracellular impact (Table 1). As in the TDP-43 and FUS introduce dysregulation of
84
happens in AD, some authors have suggested that certain RNA metabolism in cells, while misfolded SOD1
antibodies can potentially aggravate the progression of protein interferes with transport across mitochondrial
PD by contributing to an inflammatory response, likely membranes and triggers mitochondrial-dependent
76
85
through the activation of microglia. 77,78 In this sense, Wang cell apoptosis. Patients with ALS exhibit high levels of
et al. suggested that IgG antibodies associated with PD antibodies against TDP-43 compared to healthy subjects,
may synergistically activate the microglial cells, triggering suggesting a specific immune response targeting this
86
the release of toxic substances in the brain and leading to protein. However, autoantibodies against TDP-43
a high inflammatory response, when combined with the seem to decrease as the disease progresses, indicating
complement protein fragment C5a. In addition, Cao et al. that abnormal TDP-43 accumulation in nerve cells may
77
proposed that reactive antibodies intervene in microglial alter immune recognition, leading to reduced antibody
87
cell activation by interacting with Fcγ receptors involved production. Interestingly, antibodies directed to a
in NF-κB signaling, resulting in brain inflammation and specific glycine-rich domain of TDP-43 have shown
subsequent degeneration of dopaminergic neurons. promising neuroprotective effects by preventing TDP-43
78
88
Moreover, certain antibodies able to bind α-syn can interact aggregation and reducing neurofilament deposits. In
with the component of the immune system FcγRIIB, this context, reactive antibodies against misfolded SOD1
89
which regulates cellular communication in response to also inhibit protein aggregation (Table 1). In addition to
antibody binding. This interaction may influence protein these antigenic targets, high levels of antibodies directed
propagation in the brain and thus the progression of PD against specific proteins from spinal cord cells or β-actin
79
(Table 2). have also been found, affecting protein function and
cellular structure and leading ultimately to neuron
90
3.3. Other neurodegenerative diseases degeneration 90,91 (Table 2).
Beyond AD and PD, reactive antibodies have been 4. Reactive antibodies as biomarkers
identified in additional neurodegenerative disorders,
including HD and amyotrophic lateral sclerosis (ALS). Research on reactive antibodies in neurodegenerative
Understanding the role of these autoantibodies can diseases has revealed an intriguing duality: their possible
contribute to a deeper comprehension of the underlying involvement in disease development through interaction
pathological processes. with abnormal protein aggregates, and their potential as
protectors by neutralizing these accumulations. These
Huntington’s disease results from a mutation in the findings suggest a link between the immune system
huntingtin gene (HTT) leading to the production of an and neurodegenerative diseases, opening avenues
aberrant form of HTT, which accumulates in neurons for using reactive antibodies as biomarkers to better
and contributes to dysfunction and eventual cell death. understand the pathophysiological processes. Several
80
Bayram-Weston et al. uncovered the profiles of specific characteristics position reactive antibodies as potential
binding of antibodies to mutated HTT, which potentially candidates for diagnostic biomarkers in the early stages
influences the processing of mutant HTT protein aggregates of neurodegenerative diseases, when responses against
and their removal within the cell. This interaction may play misfolded proteins or abnormal aggregates may be more
a role in modulating mutated HTT levels, with potential pronounced. These include their participation in acute
implications for disease progression. Patients with HD phase responses and their easy detection in accessible
81
also display elevated levels of autoantibodies against the biological fluid samples. Among biological fluids, CSF
92
angiotensin II Type 1 receptor, which could contribute to is considered the “gold standard” for measuring reactive
vascular and neuronal imbalance in the brain (Table 1). antibodies in neurodegenerative diseases due to its
82
In addition, other authors have reported the presence of proximity to the CNS. Nevertheless, obtaining serum
93

Volume 3 Issue 1 (2024) 6 https://doi.org/10.36922/an.2058