Byline: Baruh. Polis, Abraham. Samson
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, eventually manifesting in severe cognitive dysfunction. Despite the recent proliferation of encouraging preclinical studies and clinical trials, scientific society is still far from a complete consensus regarding the AD etiology and pathogenesis. Accordingly, no approved AD-modifying therapies are currently available. Nevertheless, novel concepts predicated upon the latest discoveries and comprehension of the disease as a multifactorial disorder are paving the road to the successful AD treatment.
Accruing evidence indicates the role of systemic and brain metabolic aberrations, in addition to the canonical hallmarks, in AD pathogenesis (Polis and Samson, 2019). The up-to-date description of AD-associated pathology includes neuroinflammation, mitochondrial dysfunction, instigated apoptosis, and chronic oxidative stress. Of note, oxidative damage is one of the earliest events causing and following AD (Nunomura et al., 2001). Moreover, oxidative damage is strongly associated with neurodegenerative processes and it is a connecting factor between [sz]-amyloidosis, ?-protein hyperphosphorylation, and neuronal loss. Oxidative stress due to the disbalance between generation and elimination of reactive oxygen species (ROS) plays a key role in [sz]-amyloid-mediated cytotoxicity via a spectrum of molecular events that eventually lead to a substantial neuronal loss, which is a primary hallmark of AD, clinically manifesting in cognitive decline. In healthy individuals, excessive ROS production is counteracted by physiological antioxidant mechanisms that incessantly maintain redox homeostasis. However, these mechanisms are inadequate in the AD brain tissue and do not provide the necessary protection against highly reactive species, which disrupt membrane function, impair enzymes, break polysaccharides, and damage nucleic acids.
It is worth noting that oxidative stress characterizes normal aging as well, and leads to protein aggregation and misfolding in the brain. The hypothesis concerning the role of ROS and age-related changes in the pro-oxidant brain status, that contribute to the AD pathogenesis, was articulated long ago (Benzi and Moretti, 1995). This theory considers the extreme sensitivity of the brain to oxidative damage, due to its enormous metabolic rate together with a relatively large content of catecholamines and unsaturated lipids, as a prompting neurodegeneration factor. Recent translational studies prove the involvement of ROS in AD-associated pathology and open new treatment avenues.
Continuous life-long neuronal loss was supposed to be irreversible and cause, in some cases, cognitive impairment and neurological diseases. The brain capability to generate new neurons was confined to a distinct developmental period. However, murine and human studies have demonstrated the persistence of adult neurogenesis throughout life in several brain areas. Even though neurogenesis gradually wanes in aging animals and men, strong evidence verifies the presence of newborn cells in the brains of centenarians and AD patients (Tobin et al., 2019). Nevertheless, the density of neuronal progenitors is substantially decreased in cases of clinical AD in comparison with healthy age-matched controls, indicating severe impairment of this natural brain self-repair mechanism in AD (Moreno-Jimenez et al., 2019). Of note, some human-based postmortem studies report a significant increase in the levels of neurogenesis-related markers in AD patients compared to healthy controls (Jin et al.,...