Apoptosis is a phenomenon of programmed cell death, in which cells die sequentially at the end. The central nervous system is at fatal risk during both acute and chronic neurodegenerative disorders (NDs) [1]. The onset and prevalence of NDs such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and stroke lead to an alarming rate of increase in the number of people suffering from it. These disorders cause the degeneration of neurons oxidative stress and excessive cell-mediated proteolysis [2].

Degenerating neurons exhibit oxidative stress and excessive calcium-mediated proteolysis at the cellular level, which eventually results in apoptosis. In apoptosis, the cell and nucleus shrink and form blebbing, causing chromatin fragmentation, loss of adhesion, and rapid engulfment by phagocytosis [3]. Apoptosis also causes several biochemical changes along with morphological alterations such as DNA fragmentation, plasma membrane depolarization, lysosome permeability, and enhanced formation of reactive oxygen species (ROS) [4]. Induction of apoptosis is achieved by many methods depending on their pathways such as internal and external stimuli. Internal stimuli are triggered by activating intrinsic pathways such as abnormalities in the DNA and external stimuli are activated by cytokines such as extrinsic signaling pathways [5]. The description of normal apoptotic pathways by Guerin et al. [6] is depicted in Figure 1.

The apoptosis pathways elaborated in Figure 1 show different phases such as shrinking of the cell, membrane blebbing, the collapse of the nucleus, normal apoptotic body, and at the end leads to lysis of the apoptotic body. The descriptive pathways include two different methods of apoptosis such as intrinsic and extrinsic pathways for cascades, as depicted in Figure 2.

Proteopathies are diseases in which some proteins develop aberrant structural characteristics, which are aggregated at various cellular levels and in tissues causing the interruption of their activities [25]. The proteopathies comprise several NDs in which peculiarly accumulated proteins seem to play a vital role [26]. When the misfolded or atypical proteins accumulate in the nuclear, cytoplasmic, and extracellular enclosures, it leads to disruption of organelle and synaptic dysfunction in the nervous system. Neuronal apoptosis in neurodegenerative illnesses can be induced via oxidative stress, disruption of calcium homeostasis, and metabolic impairment, at the cellular level. The anti-apoptotic or neuroprotective signaling pathways comprising neurotrophic factors, cytokines, and conditioning responses may offset the aging effects and hereditary predisposition in the experimental models of NDs [27].

Free radical production, activation of the pathway for NO synthesis, disruption of cellular calcium homeostasis, and programmed cell death are all factors that contribute to the progression of neurodegenerative illnesses associated with glutamatergic dysfunction [28, 29]. These methods may induce mutilation of proteins, nucleic acids, and lipids, as well as open the pores of mitochondrial permeability transition, which may increase the ROS generation, energy failure degeneration, and proclamation of proapoptotic substances like Cyt c in the cytoplasm [30]. The overproduction of ROS and downregulation of antioxidant defense cause the death of NDs’ neuronal cells [31]. A variety of neurodegenerative illnesses are linked to inappropriate regulation of Wnt/β-catenin (WβC) signaling [32]. Degenerative nerve diseases are thought to contribute to the deterioration of various vital bodily functions, including memory, breathing, balance, speech, movement, and heartbeat [29]. The factors for the pathogenesis of neurogenerative disorders by Mehta et al. [33] are illustrated in Figure 3.

Apoptosis is a fundamental physiologic process that contributes to cellular homeostasis. Apoptosis (programmed cell death) is a type of physiological cellular suicide that occurs in several biological processes, including immune response, synaptogenesis, embryogenesis, and normal tissue and organ involvement. Normal brain development depends on programmed cell death. It affects the quantity and type of cells in the growing brain and spinal cord and is essential for the development of a functional neural network. In pathological circumstances, it is also partly accountable for physiological aging and the death of neurons linked to NDs [27]. Apoptotic cell death is well characterized via a sequence of morphological variations that comprise attenuation of nuclear and cytoplasmic compartments, condensation of chromatin, DNA degradation into fragments of oligonucleosomes, and an assortment of nuclear material into the vesicular apoptotic bodies [34].

Neurodegenerative disorders cause neuronal death at the cellular level as a result of oxidative stress, DNA damage as a result of endoplasmic reticulum (ER) stress, and disruption of cellular calcium homeostasis. The apparent upsurge in the lifespan of individuals and the normal age of the population is tactlessly allied to a liberal intensification in the vast number of persons having NDs [35]. Apoptosis induction via pathogenic proteins of NDs by Yang et al. [36] is described in Figure 4.

The apoptosis induction in tumor cells affects the anti-tumor efficacy of radiotherapy and chemotherapy. However, the significant adverse impact of those pro-apoptotic therapies has prompted researchers to seek out other ways to promote tumor apoptosis [38]. Antioxidants or medications that block glutamate receptors or calcium channels have traditionally been used to reduce neuronal death in NDs. Anti-inflammatory medicines and caspase inhibitors are also being utilized. The biology of neural stem cells and the “anti-aging” enzyme telomerase have also been utilized to create two distinct strategies for avoiding apoptosis and replacing damaged or dead neurons. The six-base DNA repeat sequence (TTAGGG) is added to chromosomal ends by the telomerase reverse transcriptase (TERT) enzyme, which has recently attracted a lot of attention due to its purported “anti-aging” capabilities. TERT may assist an anti-apoptotic activity in neurons by suppressing the TERT expressions or activity, which makes them more vulnerable to oxidative and excitotoxic stimuli. Conversely, overexpression of TERT protects the neurons from apoptosis [39].

Acetylcholine (Ach) is a parasympathetic neurotransmitter that also enhances synaptogenesis in living cells to influence memory and learning in people. With three approved medications (donepezil, galantamine, and rivastigmine), acetylcholinesterase inhibitors (AChEIs) are the most well-researched medications and the first-choice treatment for NDs globally. Nevertheless, the AChEIs are less valuable in the advanced stages as they necessitate a higher dose which also upsurges the risk of adverse effects. Over the years, many potential candidates like metrifonate and tesofensine came under clinical trial as AChEIs but failed at certain stages mainly due to their safety profile. Altogether, this evidence indicates an awful and unmet necessity for the development of novel AChEIs [40].

Some potent apoptotic medications used for the treatment of NDs are described in Table 1.

When subjected to excessive oxidative stress, neurons may respond adaptively to overcome the stress, or they may activate a programmed cell death pathway called apoptosis. Alterations in the ER and mitochondria, as well as the activation of cysteine proteases known as caspases, are the characteristics of apoptosis. There is mounting evidence that neurodegenerative diseases cause malfunction and neuronal death due to apoptotic biochemical pathways. Indeed, the notion that neuronal apoptotic death induction plays a crucial role in the progression of the disease, the recent advances in basic apoptosis research, and the recognition that apoptosis has a broad range of clinical applications, have prompted much of the research into investigations of intervention tactics directed at the apoptosis control or apoptosis induction in the neuronal apoptotic death program. Potential remedies can be inferred from the hypothesis that oxidative stress is shared by multiple illnesses involving increasing cell death. Among these, using neurotrophic growth factors and antioxidant molecules could be a common strategy to shield neurons from oxidative damage.

The field of apoptosis research has recently gained exciting additional insights into the mechanics of cell death programs that may perhaps contribute to the degeneration and death of neurons after acute brain trauma and the evolution of neurodegenerative diseases. The focus of this review paper will be on contemporary ideas that are important for comprehending the apoptotic death program, the mediators and regulators of cellular apoptosis, and the connection between aberrant apoptosis and the emergence of neurodegenerative illnesses. A deeper comprehension of the mechanisms underlying apoptosis may open the door to more advanced therapeutic approaches and treatment modalities that aim to regulate the neuronal apoptotic death pathway. To date, caspases and the Bcl-2 protein family are two members of the apoptotic machinery that have been the subject of much investigation. Future treatment modalities that emerge from research to more precisely identify the redox-sensitive molecular components of the neuronal apoptotic death machinery and their regulation in the various acute and chronic neurodegenerative pathologies should be challenged by the successes of these current approaches. More apoptotic inhibitors will probably be added to physicians’ daily toolkits in the coming years for treating neurologic conditions involving caspase-mediated cell malfunction and cell death.