Apoptosis leads to N/A, Neurodegeneration

During the development of the nervous system, an excessive number of neurons is produced. This massive overproduction of neurons is followed by a programmed demise of  roughly one half of the originally produced cells (Okouchi et al., 2007). The precisely controlled process is referred to as naturally occurring neuronal death which is a highly conserved cellular  mechanism in diverse organisms, ranging from invertebrate species such as the nematode (Okouchi et al., 2007), Caenorhabditis elegans, and insects, to nearly all of the studied vertebrate species (Mishima et al., 1999). Natural neuronal death is be lieved to mold the nervous system’s cellular structure and function (Okouchi et al., 2007).

As axons extend, they also bifurcate with each branch forming of its own growth cone, a process that is also regulated by apoptosis (Chen et al., 2020).  Under normal conditions, a low level of caspase maintains a balance between growth cone attraction and repulsion and inhibits axon extension; however, in PTSD, apoptosis is enhanced in key brain regions and caspase activation alters growth cone trajectory and dendritic pruning, leading to axon misguidance and dendrite degeneration. The combined outcome of these processes is the formation of fewer or incorrect synapses in PTSD that are defective in information transmission and cause abnormalities in memory and  behavior (Chen et al., 2020).

Rai, Nagendra Kumar, et al. (2013) concluded that the metal mixture arsenic, lead, and cadmium (a) induced dose-dependent modulation in the expression levels of myelin and axon proteins leading to hypo-myelination in cortex; (b) reduced axon area and myelin density in O.N.; and (c) attenuated RGC-differentiation in retina.  Apoptosis in the oligodendrocytes, axonal neurons and RGCs promoted the MM-mediated white matter damage. 

Increased apoptosis in MBP and NF damage the white matter of CNS (Petzold et al., 2011; Pun et al., 2011). In consistence, Rai, Nagendra Kumar, et al. (2013) found that the impairment in postnatal oligodendrocytes and axons further increased cellular apoptosis in the brain and O.N. The neuroaxonal degeneration in the retina also involved a rise in apoptosis in Brn3b and NF. During development, Brn3b is crucial for RGC survival, and its apoptosis may affect the expression of several genes linked with axonal integrity and function (Pan, et al., 2005). Therefore, the increased MM-related apoptosis to axonal neurons in the retina could be the fallout of RGC damage (Rai et al., 2013). Altogether, the MM, in all probability, elevates the apoptosis-mediated pruning of the myelinating cells during CNS development (Rai et al., 2013).

In the context of an Alzheimer's disease brain; compelling evidence of apoptotic involvement comes from studies of Rohn et al., (2002) who demonstrated the activation of mitochondrial and receptor-mediated  apoptotic pathways in AD hippocampal brain sections wherein active caspase 9 was co-localized with active caspase 8 (Okouchi et al., 2007). Moreover, the distribution of caspase-cleaved fragments of  tau suggests that the activation of caspases preceded the formation of neurofibrillary tangles in brains of AD patients (Chiueh et al., 2000). In addition, the intracellular amyloid beta peptide 1-42 (A beta (1-42))  has been shown to induce human neuronal cell apoptosis through Bax activation that resulted in cytochrome c release and activation of caspase 6 (Zhang et al., 2002).

The participation of apoptosis in disease pathogenesis in humans is supported by the demonstration of caspases 1, 3, 8, and 9, and cytochrome c activation in the brains of Huntington Disease patients (Kiechle et al., 2022; Teng et al., 2006; Sanchez et al., 1999).

The involvement of hippocampal neuronal apoptosis in diabetic encephalopathy has been demonstrated in diabetic animal models (Li et al., 2005), and evidence of  classical apoptosis was associated with decreased neuronal densities, and learning and cognitive deficits (Sima and Li 2005).

Cognitive impairment in BB/Wor rats is associated with evidence of classical apoptosis in the hippocampus, including DNA fragmentation, positive TUNEL staining, elevated  Bax/Bcl-x ratio, increased caspase 3 activities and decreased neuronal densities (Li et al., 2002), common features in diabetic encephalopathy.

Notable among endogenous antioxidants, is estradiol, with proven effectiveness against beta-amyloid-induced neuronal apoptosis in in vitro models of AD and PD (Gandy 2003; Yao et al., 2007).  Accelerated beta-amyloid plaque formation in animal models of AD is associated with brain estradiol deficiency (Gandy 2003). Estradiol mediates its effect by binding to the estrogen  receptor, and targets a plethora of prosurvival cellular processes (Okouchi et al., 2007). These include neuronal expression of Bcl-2 members, upregulation of antioxidant proteins such as TRX, MnSOD, and nNOS, Akt signaling, and inhibition of transcriptional and apoptotic activity of the APPct complex (Yao et al., 2007; Bao et al., 2007; Chiueh et al., 2003; Koh et al., 2006). Melatonin is another naturally occurring neuroprotectant  that decreases amyloid fibril formation (Pappolla et al., 1998) and attenuates neuronal apoptosis in in vitro and animal models of AD and PD (Chiueh et al., 2000; Deigner et al., 2000; Matsubara et al., 2003). Its neuroprotective effects appear to be  the result of antioxidant and anti-amyloidogenic properties (Pappolla et al., 2002) and are independent of binding to membrane receptors (Okouchi et al., 2007).

While the molecular mechanisms underlying neuronal apoptosis and diabetic encephalopathy remain unresolved, it appears that diabetes-associated perturbations in the  insulin/IGF system and hyperglycemia may play prominent roles (Li and Sima 2004).