**Conflict of interest**

*Amyloid Diseases*

tive stress related studies.

**5. Conclusions**

Aβ pathology [95]. ApoE interaction with Aβ is modulated by metals [93]. There are two key requirements for metal interactions in dementia-either supplementation or chelation [83]. Metal chelators can help solubilization of Aβ plaques. Effects of chaperones on metal ions need to be carefully curated to maintain metal homeostasis in brain and other organs of nervous system. Several endogenous brain proteins show potential protective response against ROS in diseased brain, including β-trace protein, which is the second most abundant protein in CSF. Competitive binding of metal ions by chaperone proteins may be advantageous in decreasing generation of ROS by-products. Overexpression of metal-affinity proteins have been shown, as example of iron-binding ferritin. Antioxidant alpha-tocopherol has been reported to potentially slow AD progression in addition to action of metal chelators such as clioquinol and desferrioxamine [92]. L-PGDS scavenges ROS and in process protects against neuronal cell death with its ligand binding function intact [96]. It also reduces cytotoxicity mediated by oxidation of heme metabolites such as bilirubin [97]. We have found that L-PGDS can directly interact with Aβ-heme complex and lower its peroxidase activity (to be published). Other non-proteolytic chaperones such as α2M, clusterin and haptoglobin, also show neuroprotective potential in similar manner as L-PGDS and are good candidates for more comprehensive oxida-

Alzheimer's disease is a debilitating neurodegenerative condition and is projected to be a major risk factor for global population by the year 2050 [98]. One of the key theories, known as "amyloid cascade hypothesis" postulates that oligomerization of amyloid-β (Aβ) in brain is the key pathological event in AD [99]. Although complete explanation of causation in AD is yet to be established, it has been universally accepted that amyloidosis (perhaps provoked by environmental factors) plays a crucial role in AD progression [99–101]. Conformational alterations in Aβ which lead to its conversion from soluble peptide to insoluble aggregates are considered as a key mechanism in pathogenesis of neurodegenerative diseases such as AD [102]. Early amyloid aggregates can act as biomarkers in most dementia related maladies and associate observed clinical symptoms to underlying pathophysiological mechanisms. Till date, we do not have any therapeutic solution for aggregation of amyloids. Current gold-standard biomarkers in neurodegeneration are neuroimaging systems of degeneration and detectable clinical symptoms represent pathological changes causing irreversible damage to nervous system [33, 36]. Success of theranostic efforts will rely on rational drug design based on a proper understanding of molecular structures and mechanisms involved in aggregation. Aβ mediates AD pathology through direct inhibition of neuronal interactions and signaling cascades, and triggers oxidative stress in the process. Here we have discussed mechanisms of action of amyloid chaperones with focus on Aβ chaperones to better understand their modus operandi. Apart from the protein quality control machinery and housekeeping complexes responsible for maintaining general proteostasis, we have discussed importance of other endogenous chaperones which step up in time of crisis, often as response to stress stimuli. Proteins such as L-PGDS, clusterin, α2M have are involved in many physiological processes, with elusive function as amyloid chaperones. These proteins can provide alternative mechanisms to control amyloid aggregates in events of failure of intracellular Hsp complexes and proteasome machinery. Additionally, their affinity to redox active components may provide additional protective mechanisms against Aβ mediated

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oxidative stress.

Authors declare no conflict of interest.
