Neurodegeneration defines as progressive loss of function and structure of neurons which further can lead to death of neurons in different areas of the nervous system. It is well known the damage or die neurons cannot be replaced or reproduced by the body, hence, the progressive loss of nerve cells can cause neurological and neuropsychological features in many incurable and debilitating neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson disease (PD) and Amyotrophic lateral sclerosis (ALS) (Aguzzi A and O’ Connor, 2010). This showed the urgent need to explore more effective therapeutic findings to combat the devastating diseases.
Neurodegenerative diseases can be classified based on primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormality. Findings showed there is a gap in lifetime risk between men and women with 2 and 1.3 % respectively (Elbaz et al., 2002). The risk factors involve in neurodegenerative diseases is often multifactorial mainly by gene-environmental interactions. Broadly, the occurrance of neurodegenerative development increasing with age, familial association, Down syndrome and apolipoprotein E4 allele (Cedazo-Mínguez A and Cowburn RF, 2001).
The established pathological hallmark in most of the neurodegenerative diseases related with impaired proteostasis and autophagy activity, subsequently, contributing to aggregation of misfolded proteins that reside in different cellular and subcellular compartment. In AD, aggregation of senile plaque composed mainly amyloid ? and neurofibrillary tangles (NFTs) in hippocampus and cortex (Armstrong, 2009)
Autophagy or “self-eating” involves in most intracellular machinery control of misfolded protein and maintain proteostasis. The major function mainly to remove the damaged organelles in the compartment and degradation of long-lived proteins which are too large to engulf by proteosomes. It can be classified into microautophagy (Marzella et al., 1981), cheparone-mediated autophagy (Kaushik and Cuervo, 2012) and the most predominant form macroautophagy (Settembre et al., 2013). The autophagy activity is enhanced by physiological or pathological process like cell death, microorganism invasion and tumor suppression (Glick et al., 2013). In addition, stress impact to the cell such as nutrient starvation, inflammation, and hypoxia (Francois et al., 2013) also can exaggerate the autophagy process. In advancing aged the function is said to be suppressed (Rubinsztein et al., 2011). The encapsulated lipid bilayer membrane structure known as lysosome (Xu and Ren, 2015) responsible for autophagy process as it contains variety of hydrolase enzymes (Xu and Ren, 2015). The amino acid byproduct from ‘self-eating’ will provide energy source to the cell for another protein synthesis (Meijer et al., 2015). Yet, proteostasis is carried by proteosome and it plays a key role in cell cycle, immune response and intracellular degradation pathway (Ciechanover and Schwartz, 1998).
So, dysfunction of both organelles caused dysregulation of autophagy and proteostasis process further lead to accumulation of noxious and unwanted protein intracellularly. Menzis FM et al., 2015 proposed in their study regarding regulation of autophagy can act as potential therapeutic agent in most neurodegenerative diseases.
Addition pathology suggested by Francois et al., 2013 showed connection between neuroinflammation and autophagy in causing the diseases. It works in such a way that under severe inflammation within the brain cells elicited by IL-1? will cause activation of autophagy in microglia grown in cultures. Indeed, it was shown also following stress induced hypertension condition caused neuroinflammation and autophagy (Du et al., 2017). Dysregulation of autophagy cause excitation of microglial activity including secretion of inflammatory mediators like IL-1?, toxic reactive oxygen species (ROS) (Ye et al., 2017), mTOR and Becn1 in vivo (Francois et al., 2014) which will make inflammation in the brain worsen.
MTOR pathway is initiated mainly by a nutrient and growth factor. It responsible for autophagy regulation (Jung et al., 2010). In AD, reduced mTOR signals lead to reduction in the level of ? amyloid (Caccamo et al., 2014) and tau protein (Tang et al., 2015). Spilman et al., 2010 showed study on mouse model of AD by blocking the mTOR pathway using rapamycin relieved cognitive deterioration, reduced amyloid aggregation and increased lifespan of animals (Harrison et al., 2009). Besides all above mention pathogenesis, the expression of stimulators which favours autophagy plays an important role in maintaining optimum environment inside the brain cells include autophagy-related 7 (Ohsumi, 2014), antiapoptotic factor BCL2 (Decuypere et al., 2012), Beclin/BECN1/ATG6 (Francois et al., 2014), clusterin (Zhang F et al., 2014), cathepsin D (Dean, 1975), FOXO1 (Xu et al., 2011), inositol 1,4,5-trisphosphate receptor type 1 (Santulli and Marks,2015), presenilin 1 (De strooper et al., 1998), alpha synuclein (Uhlen et al., 2015) and ubiquilin 1(N’Diaye et al., 2009). Whereas, CDK5 (Wong et al., 2011) and glial fibrillary acidic protein (Yang and Wang, 2015) will cause inhibition of autophagy through distinct mechanism.