Does oxidatively damaged DNA drive amyloid-β generation in Alzheimer’s disease? A hypothesis

The molecular basis of the dichotomous functionality of MAP4K4 in proliferation and cell motility control in cancer

“…In AD, upstream β-secretase 1 (BACE1) expression and amyloid-β (Aβ) deposition are driven by ectopic oxidative stress via multiple mechanisms, including c-Jun N-terminal kinase (JNK) activation ( 43 , 44 ). It was thus postulated that oxidatively damaged DNA might induce MAP4K4, thereby sensitizing the brain to oxidative stress-induced JNK activation and BACE1 induction ( 45 ).…”

Virus-Like Cytosolic and Cell-Free Oxidatively Damaged Nucleic Acids Likely Drive Inflammation, Synapse Degeneration, and Neuron Death in Alzheimer’s Disease

“…Mechanistically linking cytosolic and cell-free nucleic acids and innate inflammation, ectopic DAMP and pathogen-associated molecular pattern (PAMP) nucleic acids provoke antiviral IRF3/type-I interferon and/or inflammatory NF- κ B signaling in part by oligomerizing with several cytosolic innate immune pattern-recognition receptors (PRR) that were upregulated in AD patients’ brains, including the Nucleotide-binding oligomerization domain-Like Receptor Pyrin domain-containing 3 (NLRP3) inflammasome [ 24, 25, 43–50 ], Protein Kinase double-stranded RNA-activated interferon-induced (PKR) [ 51–55 ], STING downstream of cGAS [ 56, 57 ], the Absent In Melanoma 2 (AIM2) inflammasome [ 1, 57, 58 ], and the Interferon-Inducible Protein 16 (IFI16) inflammasome [ 21, 57, 58 ].…”

“…AD is caused rarely by specific mutations, and commonly by the combination of numerous diverse risk factors, chiefly aging and being heterozygous or homozygous for the APOE4 allele. Indeed, many if not all AD causal mutations and risk factors— including aging and APOE4 genotype— have been associated with increased oxidative stress/damage/injury [ 1, 2, 30–32 ]. Furthermore, oxidatively damaged lipids and nucleic acids have been shown to accumulate in PCAD, MCI, and AD patients’ brains [ 18–20, 39–41, 114–116 ], and oxidatively damaged proteins have been shown to accumulate in MCI and AD patients’ brains [ 117–119 ].…”

“…Oxidative stress, inflammation, and amyloid-β (Aβ) signaling are core Alzheimer’s disease (AD) hallmarks that can cause each other and other AD hallmarks experimentally [ 1, 2 ]. Paradoxically though, most clinical trials for AD patients of Aβ-lowering, antioxidant, anti-inflammatory, and antimicrobial agents failed, and even the few that met their primary endpoints or even slowed early-AD progression failed to stop or reverse AD progression [ 2–7 ].…”

“…Based on the currently available directly relevant neuropathology [ 12, 15, 18–25 ], neuronal cell culture [ 21, 26 ], rodent [ 21, 26 ], genome-wide association [ 27, 28 ], epidemiological [ 1, 2, 26, 29–32 ], and biomarker studies [ 33–37 ], plus the only currently available relevant clinical experiment [ 38 ], it appears likely that the virus-like, damage-associated molecular pattern (DAMP) cytosolic and cell-free oxidatively damaged nucleic acids accumulated in AD patients’ brains, and the innate immune system reacting to them as if they were viruses, contribute non-trivially to multiple aspects of AD pathophysiology, including neuroinflammation, synaptotoxicity, and neurotoxicity.…”