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Advanced Neurology Genomic insights into Alzheimer

A total of 36 toxic T-cell epitopes were linked to the While 32 pathogenic mutations have been described for
M722K (24.83%), Arctic (24.66%), Austrian (24.66%), the APP gene , little is known about whether specific
[41]
A673V (24.49%), Osaka (24.49%), and V717G (24.49%) physicochemical patterns associated with these mutations
mutations; 35 to the Tottori (24.14%), Iranian (23.97%), directly affect clinical and neuropathological outcomes in
French (23.97%), and Iowa (23.81%) mutations; 34 to the fAD. The APP gene is encoded by 18 exons that undergo
T719N (23.45%), Indiana (22.97%), and Iberian (22.82%) alternative splicing to produce APPs ranging in size
mutations; 33 to the Australian (22.76%), London from 695 to 770 amino acids. Among the 32 pathogenic
(22.60%), Swedish (22.45%), and Flemish (22.45%) mutations described for the APP gene, 26 are recognized as
mutations; and 31 to the Taiwanese (21.38%) and V717L pathogenic missense mutations located within or adjacent
(20.95%) mutations (Table S4). to Aβ, generated from APP through the sequential cleavage
of β-secretase and γ-secretases .
[42]
3.6. Comparison of B- and T-cell epitopes toxicity
burden with clinical and neuropathological It has been demonstrated that a double mutation
outcomes located at the N-terminus of Aβ, specifically at the
β-secretase cleavage site in exon 16 of APP770 at codons
A thorough literature search was conducted to delineate 670 and 671, results in an increased production of total Aβ.
the clinical symptoms and neuropathology associated Moreover, the pathogenic mutation APP E693Q, identified
with each identified APP mutation (Tables 4 and 5). in a Dutch family with inherited cerebral hemorrhage
Subsequently, after collating and analyzing the toxicity with amyloidosis caused by Aβ , has been reported.
[43]
results of both B and T cell epitopes for each mutation Mutations within the Aβ domain have been shown to alter
(as well as wild-type APP), three distinct categories were APP processing, leading to an increased hydrophobicity
established to define the toxicity burden based on the [44,45]
cumulative volume of toxic epitopes (toxicity determined of secreted Aβ species . Aβ42 mutations are associated
according to ToxinPred server for both B and T cell linear with progressive dementia, senile plaques, neurofibrillary
[46]
epitopes). Mutations demonstrating more than 35 toxic tangles, and neuronal cell loss . Interestingly, mutations
epitopes were classified as having a high toxicity burden associated with an increase in total Aβ also contribute to
(seven mutations in total: A673V, Osaka, Arctic, Austrian, cerebral amyloid angiopathy (CAA) and are associated
[47,48]
German, V717G, M722K). The remaining mutations, with cerebral hemorrhages and stroke . These findings
featuring 34 – 35 toxic epitopes, were considered to highlight the importance of the amino acid composition
have a moderate toxicity burden (8 mutations in total: of the Aβ by-products and their direct influence on the
Tottori, Iowa, Iranian, French, Iberian, Indiana, T719N, pathology and kinetic of pathological Aβ. Nonetheless,
Australian). All mutations with fewer than 34 toxic to our knowledge, little attempt has been made to
epitopes were categorized with a low toxicity burden (five study the influence of the physicochemical properties
mutations in total: Swedish, Taiwanese, Flemish, London, of APP/Aβ-bearing mutations on disease progression,
V717L), along with wild-type APP (toxicity burden = 31). pathogenesis, clinical presentation, Aβ kinetics, and
toxicity, among other aspects.
An increase in toxicity burden was correlated to an
increase in neuropathological changes as reported in In this study, we investigated the relationship between
the literature, specifically an increase in Aβ deposition 20 fAD mutations and the physicochemical properties
(identified in 57% of mutations with high toxicity burden) of the corresponding APPs. Our aim was to examine
and the presence of amyloid plaques and neurofibrillary the specific effects of these mutations on both clinical
tangles (identified in 43% of mutations with high toxicity and neuropathological outcomes. We sought to identify
burden) among study participants (Table 5). However, no associations between clinical symptoms, neuropathology,
correlation was identified between clinical presentation and the physicochemical features of the 20 APP mutations.
(symptom presentation, disease burden, or age of onset) Various clinical symptoms, including cognitive decline,
and the burden of epitope toxicity. hemorrhage, seizures, myoclonus, autonomic failure,
aphasia, behavioral abnormalities, dyscalculia, and
4. Discussion pyramidal signs, were found to be associated with different
APP mutations. Notably, all 20 APP mutations were linked
fAD arises from mutations in the APP and PSEN genes . to cognitive impairment.
[6]
The clinical presentation and neuropathological features
of both sporadic AD (SAD) and fAD display a striking Similarly, cognitive impairment, seizures, and
resemblance. Therefore, investigating the molecular events hemorrhage have been linked to the Flemish
underlying fAD is critical for understanding disease mutation [14,15,49,50] . On the other hand, the Iranian mutation
pathogenesis and developing disease-modifying therapies. exhibited cognitive impairment, seizures, autonomic

Volume 2 Issue 4 (2023) 13 https://doi.org/10.36922/an.1734