Umair Ashraf
Genomic Instability and Oxidative Stress Induced Mutagenesis
The mitochondrial genome (mtDNA) and nuclear DNA (nDNA) undergo direct and indirect oxidative modifications via ROS, primarily in the form of •OH and O₂. The induced lesions at key loci—such as 8-hydroxy-2 -deoxyguanosine (8-OHdG) and thymine glycol—interfere with normal base pairing and lead to misalignments during DNA replication. Key repair proteins (e.g., DNA polymerase β, XRCC1, PARP-1) exhibit compromised function due to acetylation of histones (H3K9ac, H4K16ac) and hypermethylation of CpG islands, further driving the amplification of mutations.This dysregulation primes the DNA repair machinery for failure, resulting in an accumulation of single-nucleotide polymorphisms (SNPs) in critical genes like PGC-1α, SOD2, and PARP-1—genes central to mitochondrial biogenesis, antioxidant defense, and DNA repair. In AD, the malfunction of the oxidative stress response pathways leads to an increased vulnerability of the nuclear genome to further insult, culminating in a state of genomic instability.
Ribosomal Dysfunction and Protein Synthesis Errors
The ribosome itself is not immune to oxidative damage. The rRNA sequence, particularly the 18S rRNA region, can undergo oxidative guanine modifications, impairing the ribosomal decoding process. The misincorporation of amino acids (e.g., aspartic acid at positions where proline should occur in C-terminal regions) leads to protein misfolding, reducing translation fidelity. Specifically, the failure to correctly incorporate proline at proline-rich stretches leads to the reduced functional state of proteins involved in neuronal synaptic signaling.These translational defects are further amplified by the accumulation of misfolded proteins that overwhelm the proteasomal degradation pathways and initiate UPR signaling via the IRE1α-XBP1 cascade, triggering a retrograde response from the ER to the nucleus. This cascade eventually leads to the upregulation of pro-apoptotic factors such as CHOP (C/EBP homologous protein) and ATF3, causing irreversible neuronal damage.
Amyloid Precursor Protein (APP) Cleavage and Aβ42 Aggregation Pathway
Amyloid precursor protein (APP) undergoes sequential cleavage by β-secretase (BACE1) at the Asp 672 position and γ-secretase at its C-terminal region. BACE1 cleaves APP at Ala 649, creating the soluble APPβ and a membrane-bound C99 fragment. The latter is then processed by γ-secretase, a multi-subunit complex, involving presenilin 1 (PS1) and presenilin 2 (PS2), at the ε-cleavage site. This generates Aβ peptides, particularly Aβ40 and Aβ42, with the latter being more prone to aggregation due to its increased hydrophobicity.The aggregation of Aβ42 into β-sheet-rich fibrils leads to the formation of amyloid plaques. The highly stable β-sheet structure of these fibrils impairs synaptic signaling by disrupting synaptic vesicle recycling, reducing synaptic glutamate release, and contributing to excitotoxicity. The amyloid plaques also serve as seeding templates for tau misfolding, exacerbating tau aggregation and subsequent neurofibrillary tangle formation.

Tau Isoform Selection and Alternative Splicing Dysregulation
Tau undergoes alternative splicing primarily at exon 10, resulting in the generation of tau isoforms with differing repeat domains. These isoforms, 3-repeat (R3) and 4-repeat (R4) tau, are subject to hyperphosphorylation in Alzheimer’s. Under normal conditions, R3 isoforms are less aggregation-prone due to their reduced proline-directed phosphorylation capacity, while R4 isoforms—predominantly expressed in neurodegenerative diseases—exhibit increased aggregate propensity.This splicing dysregulation is mediated by splicing factors such as SR proteins (e.g., SF2/ASF) and hnRNPs, which bind to the pre-mRNA of tau and modulate exon inclusion. A shift toward R4 isoforms, and their consequent aggregation into paired helical filaments (PHFs), is a critical pathologic feature of AD. The K18 domain within tau plays a central role in its fibrillogenesis, where the phosphorylation at Ser202 and Thr205 promotes the formation of β-sheet structures that self-assemble into insoluble aggregates.These aggregates propagate through prion-like mechanisms, where tau fibrils seed the aggregation of soluble tau proteins in neighboring neurons. The resultant neurofibrillary tangles (NFTs) disrupt axonal transport, leading to the collapse of microtubule stability.
Tau Seeding and Amyloid Interactions
Aβ42 aggregates, composed of β-sheet rich amyloid fibrils, have been shown to seed tau aggregation. The interaction between Aβ42 and tau involves a co- aggregation mechanism where tau’s K18 domain undergoes a conformational change upon contact with the Aβ fibrils, increasing its aggregation potential. The C-terminal fragment of tau (CTF83), formed after calpain cleavage, associates with Aβ deposits, further promoting tau misfolding.Tau seeds act as nucleation centers that recruit misfolded tau from the cytoplasm, catalyzing the polymerization of tau filaments. This cross-seeding between Aβ42 and tau accelerates the pathological spread across the neocortex and hippocampus, enhancing cognitive decline.
Mitochondrial Dysfunction and Calcium Overload in AD
Mitochondrial dysregulation is a central feature of AD, as mitochondrial calcium dysregulation plays a crucial role in neuronal death. The MCU (Mitochondrial Calcium Uniporter) channel is responsible for mitochondrial calcium uptake. In AD, excessive calcium influx into mitochondria triggers a cascade of events, including activation of calpains, caspases, and catalytic proteases, which further degrade neuronal structures.The dysfunctional mitochondria also exhibit impaired ATP production, further exacerbating the energy deficit and contributing to synaptic failure. Additionally, oxidative stress generated by impaired oxidative phosphorylation leads to the generation of ROS within mitochondria, which amplifies the damage to both lipid membranes and nucleic acids.
Synaptic Dysfunction and Excitotoxicity: NMDA Receptor Signaling
The NMDA receptor (NMDAR), a glutamate-gated ion channel, plays an essential role in synaptic plasticity, but its overactivation in AD leads to excitotoxicity. Excessive activation of the NMDA receptor leads to calcium influx into neurons, which triggers downstream signaling pathways involving calcineurin, NO synthase, and cAMP-response element binding (CREB) proteins. This calcium overload activates a host of proteases, including calpain, which degrades synaptic scaffolding proteins and impairs synaptic plasticity.Moreover, the activation of NMDA receptors contributes to the upregulation of neuroinflammatory cytokines (e.g., TNF-α, IL-1β), which exacerbate neuronal dysfunction. The disruption of retrograde signaling through BDNF and its receptors (TrkB) further impedes synaptic integrity, resulting in a significant decline in cognitive function.
The Article has been written by Author “Umair Ashraf” who is a Master’s student in Clinical Psychology with a dedicated focus on neural networks, brain chemistry, and their broader societal implications. He can be reached at Umairvani07@gmail.com