Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

Abstract

Neuronal microtubule (MT) tau protein provides cytoskeleton to neuronal cells and plays a vital role including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediates MT destabilization resulting in axonopathy and neurotransmitter deficit, and ultimately causing Alzheimer's disease (AD), a dementing disorder affecting vast geriatric populations worldwide, characterized by the existence of extracellular amyloid plaques and intracellular neurofibrillary tangles in a hyperphosphorylated state. Pre-clinically, streptozotocin stereotaxically mimics the behavioral and biochemical alterations similar to AD associated with tau pathology resulting in MT assembly defects, which proceed neuropathological cascades. Accessible interventions like cholinesterase inhibitors and NMDA antagonist clinically provides only symptomatic relief. Involvement of microtubule stabilizers (MTS) prevents tauopathy particularly by targeting MT oriented cytoskeleton and promotes polymerization of tubulin protein. Multiple in vitro and in vivo research studies have shown that MTS can hold substantial potential for the treatment of AD-related tauopathy dementias through restoration of tau function and axonal transport. Moreover, anti-cancer taxane derivatives and epothiolones may have potential to ameliorate MT destabilization and prevent the neuronal structural and functional alterations associated with tauopathies. Therefore, this current review strictly focuses on exploration of various clinical and pre-clinical features available for AD to understand the neuropathological mechanisms as well as introduce pharmacological interventions associated with MT stabilization. MTS from diverse natural sources continue to be of value in the treatment of cancer, suggesting that these agents have potential to be of interest in the treatment of AD-related tauopathy dementia in the future.

UNC-45A Is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

“…Interestingly, Tau, a MAP that stabilizes MT via preventing MT severing [ 44 ], is largely expressed in the brain, its hyperphosphorylation is associated with Alzheimer’s disease (AD) and other tauopathies [ 45 , 46 , 47 , 48 , 49 , 50 ], and it is abnormally expressed in ovarian cancer [ 51 , 52 ]. Importantly, drugs targeting MT stability are an established anti-cancer approach for ovarian cancer [ 53 , 54 ] and stabilization of neuronal MTs can attenuate neurodegenerative in mouse models of AD and other tauopathies [ 55 ]. In this context, our results suggest that UNC-45A may play a role in the physiology of the central nervous system as well as in neurodegeneration.…”

UNC-45A is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

“…Interestingly, Tau, a MAP which stabilizes MT via preventing MT severing ( 41 ) is largely expressed in brain, its hyperphosphorylation is associated with Alzheimer’s disease (AD) and other tauophathies ( 42–47 ), and is abnormally expressed in ovarian cancer ( 48, 49 ). Importantly, drugs targeting MT stability is an established anti-cancer approach for ovarian cancer ( 50, 51 ) and stabilization of neuronal MTs can attenuate neurodegenerative in mouse models of AD and other tauopathies ( 52 ). In this context, our results suggests that UNC-45A may play a role in the physiology of the central nervous system as well as in neurodegeneration.…”

Forskolin, an Adenylcyclase/cAMP/CREB Signaling Activator Restoring Myelin-Associated Oligodendrocyte Destruction in Experimental Ethidium Bromide Model of Multiple Sclerosis

“…During the 35th day of the experiment, a hidden platform was added to the Morris water maze apparatus and allowed the rats to swim about for 120 s to record the time spent in the target quadrant of the apparatus (TSTQ). The TSTQ shows that memory consolidation has occurred after teaching [ 32 ].…”