Umair Ashraf
Genomic Instability and Oxidative Stress
In Alzheimer’s disease (AD) and other tauopathies, genomic instability caused by oxidative stress plays a critical role. Reactive oxygen species (ROS) such as hydroxyl radicals (•OH) and superoxide (O₂⁻) cause oxidative modifications to mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). These modifications result in lesions like 8-hydroxy-2′-deoxyguanosine (8-OHdG) and thymine glycol, disrupting base pairing and causing DNA replication errors.
DNA repair proteins, including DNA polymerase β, XRCC1, and PARP-1, are impaired by histone acetylation (H3K9ac, H4K16ac) and CpG island hypermethylation, compromising their function. This results in an accumulation of single-nucleotide polymorphisms (SNPs) in genes critical to mitochondrial biogenesis (PGC-1α), antioxidant defense (SOD2), and DNA repair (PARP-1). The oxidative stress response dysfunction exacerbates nuclear genome instability, leaving neurons vulnerable to damage.
Ribosomal Dysfunction and Protein Synthesis Errors
Oxidative damage also affects ribosomal RNA (rRNA), especially the 18S rRNA region, impairing the ribosome’s ability to decode genetic information accurately. Errors in amino acid incorporation during protein synthesis—such as replacing proline with aspartic acid—lead to protein misfolding. This disrupts neuronal synaptic signaling and overwhelms proteasomal degradation pathways, activating the unfolded protein response (UPR).
The UPR, mediated by the IRE1α-XBP1 pathway, initiates a cascade that upregulates pro-apoptotic factors like CHOP and ATF3, culminating in irreversible neuronal damage.
Amyloid Precursor Protein (APP) Cleavage and Aβ42 Aggregation
Amyloid precursor protein (APP) undergoes sequential cleavage by β-secretase (BACE1) and γ-secretase, producing amyloid-beta (Aβ) peptides, primarily Aβ40 and Aβ42. Aβ42, being highly hydrophobic, aggregates into β-sheet-rich fibrils, forming amyloid plaques. These plaques disrupt synaptic signaling, impair vesicle recycling, and contribute to excitotoxicity.
Amyloid plaques also promote tau misfolding, triggering the formation of neurofibrillary tangles (NFTs). This interaction exacerbates neuronal dysfunction, significantly contributing to cognitive decline in AD.
Tau Isoform Dysregulation and Aggregation
Tau protein undergoes alternative splicing at exon 10, producing 3-repeat (R3) and 4-repeat (R4) isoforms. R4 tau, predominantly expressed in neurodegenerative conditions, is more prone to aggregation. Dysregulated splicing, mediated by SR proteins and hnRNPs, results in a shift toward R4 tau isoforms.
Hyperphosphorylated tau aggregates into paired helical filaments (PHFs), forming NFTs. This aggregation, driven by phosphorylation at Ser202 and Thr205, disrupts axonal transport and microtubule stability, impairing neuronal function.
Tau Seeding and Amyloid Interactions
Aβ42 aggregates serve as seeds for tau aggregation, promoting tau’s conformational changes and accelerating its misfolding. Tau fragments like CTF83 enhance this process, propagating tau pathology through prion-like mechanisms. This cross-seeding intensifies the spread of neurodegeneration across the neocortex and hippocampus.
Mitochondrial Dysfunction and Calcium Overload
Mitochondrial dysfunction is a hallmark of AD, with calcium dysregulation playing a key role. The mitochondrial calcium uniporter (MCU) allows excessive calcium influx, triggering calpain and caspase activation. These enzymes degrade neuronal structures, impair ATP production, and increase oxidative stress.
The resulting energy deficit and ROS generation further damage lipid membranes and nucleic acids, amplifying neurodegeneration.
Synaptic Dysfunction and Excitotoxicity
Overactivation of NMDA receptors in AD leads to excitotoxicity. Excessive calcium influx activates calcineurin, nitric oxide synthase, and CREB proteins, disrupting synaptic plasticity. This cascade degrades synaptic scaffolding proteins and impairs retrograde signaling through BDNF and TrkB receptors.
Neuroinflammatory cytokines such as TNF-α and IL-1β exacerbate synaptic dysfunction, further reducing cognitive function.
Conclusion
The intricate interplay of oxidative stress, genomic instability, protein misfolding, and mitochondrial dysfunction drives the progression of Alzheimer’s disease. Understanding these molecular mechanisms is essential for developing effective therapies to combat this devastating neurodegenerative condition.
(Note:Umair Ashraf is a Master’s student in Clinical Psychology with a keen interest in neural networks, brain chemistry, and their societal implications. He can be reached at Umairvani07@gmail.com.)
