Ultrastructural Study Reveals that Mouse Hippocampal Neurons are More Protected than the Cerebrocortical Neurons from Age Related Cytological Alterations

The “free radical theory of aging” proposed by Harman postulates that free radicals cause damage to cellular macromolecules and thereby deteriorates cellular functions [1]. The brain is more susceptible to oxidative stress due to high content of unsaturated fatty acids; high oxygen consumption per unit weight; high content of lipid peroxidation key ingredients (iron and ascorbate); and the scarcity of antioxidant defenses systems [2]. Oxidative damage to the brain leads to dementia. Even smaller impairment in the neural tissue increases the susceptibility to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis [3]. Neurodegenerative diseases are characterized by decline in the normal antioxidant defense mechanisms that leads to deleterious oxidative changes [4]. Since, mitochondria are involved in redox reactions associated with cellular respiration, they are the source of Reactive Oxygen Species [ROS] [5-6]. Superoxide radicals are generated during mitochondrial metabolism get dismutated to hydrogen peroxide [7] which react with ferrous ions to generate most dangerous hydroxyl radicals [8]. The free radicals cause oxidative damage to mitochondrial DNA and affect mitochondrial metabolism [9-10]. The damaged mitochondria produce less ATP and more free radicals thereby increases the oxidative stress [11]. The free radicals react with membrane lipids and cause oxidative damage [12-13]. Except ribosome’s, all the cell organelles are membrane bound. Thus, membranes of virtually all cell organelles are potentially targets of oxidative damage. Damage to membrane structure affects ion transporters, signal transduction, membrane potential and membrane permeability which ultimately perturb cellular metabolism that eventually lead to cell death [14]. Oxidative damage to proteins cause structural modifications such as protein cross linking, change in three dimensional structure of proteins [15-16]. This leads to loss of functions of the proteins. Oxidatively modified biomolecules become resistant to lysosomal degradation and get accumulated in the lysosomes as intracellular debris called as lipofuscin granules [17-18]. ROS also cause oxidative damage to DNA resulting into genome instability and affect transcription [19-20]. ROS and mitochondria are involved in pathogenesis of neurodegenerative diseases [21]. Lipid peroxidation (LP) is the oxidative modification in the polyunsaturated fatty acids (PUFAS) [22]. During this process, large numbers of toxic byproducts are generated which alter the cellular functions and ultimately affect the cell survival [23].