ADVANCES IN Tau PROTEIN INHIBITORS FOR ALZHEIMER’S DISEASE – A REVIEW

INTRODUCTION TO ALZHEIMER’S DISEASE:
Alzheimer’s disease was originally defined as presenile dementia, but it now appears that the same pathology underlies the dementia irrespective of the age of onset. AD is alluded to dementia which happens with no reason, for example, stroke, cerebrum injury or liquor. It is perpetual neurodegenerative ailment that more often than not begins gradually and deteriorates after some time. It is the reason for 60% to 70% of instances of dementia. The most widely recognized side effect is loss of memory at little timeframe and it is seen in beginning period (here and now memory misfortune). As the sickness progresses, manifestations can incorporate issues with dialect, confusion (counting effectively getting lost), inclination swings, loss of inspiration, not overseeing self care, and behavioral issues. In spite of the fact that the speed of movement can shift, the normal future after determination is three to nine years. The sickness course is divided into four stages, with a progressive pattern of cognitive and functional
impairment:
1) Pre- dementia
2) Early
3) Moderate
4) Advanced

STATISTICS: An expected 5.4 million Americans of the sum total of what ages have Alzheimer’s illness in 2016. This number incorporates a 5.2 million individuals age 65 and more seasoned, and

roughly 200,000 people under age 65 who have more youthful beginning Alzheimer’s. 1 in 9 individuals age 65 and more seasoned (11 %) has Alzheimer’s sickness. Around 33% of individuals age 85 and more established (32%) have Alzheimer’s malady. Eighty-one percent of individuals who have Alzheimer’s ailment are age 75 or more established. . A larger number of ladies than men have Alzheimer’s sickness and different dementias. Just about 66% of Americans with Alzheimer’s are ladies. Of the 5.2 million individuals age 65 and more seasoned with Alzheimer’s in the Unified States, 3.3 million are ladies and 1.9 million are men. In view of assessments, among individuals age 71 and more established, 16% of ladies have Alzheimer’s sickness and different dementias contrasted and 11% of men.

PATHOPHYSIOLOGY OF ALZHEIMER’S:

There are mainly two pathways for the metabolism of amyloid precursor proteins (APP) i.e. physiological pathway and amyloidogenic pathway. In the physiological pathway APP in the presence of α-secretase enzyme and gets activated which in turn activates the function of growth factors. In the amyloidogenic pathway the APP in presence of β &ϒ- secretase enzyme converts it to two different forms Aβ-40 and Aβ-42 in alzheimer’s the concentration of Aβ-42 is more thus on aggregation this both proteins
they form oligomers and further converted to amyloid plaques which causes inflammation, mitochondrial damage and creates oxidative stress and thus causes

neuronal death. Alternatively the oligomers formed combines with kinase in turn activating tau to activated tau -pyrophospho proteins and reversible
reaction via phosphatase which in turn forms neurofibrillary tangles and thus causes neuronal death.

PATHOPYSIOLOGY OF TAU PROTEINS ON AD AND INHIBITION OF TAU AGGREGATION:

As seen in the pathophysiology of the AD the formed oligomers can be stopped for further division by many different ways kinase inhibitors are used which stops the activation of the tau proteins. Then methylene blue is also used for the treatment and folic acid is also used for the treatment.

RECENT ADVANCES IN DRUGS USED IN ALZHEIMER’S DISEASE:

There are currently 5 inhibitors for the treatment of AD under research namely: crenezumab, ACI-24, ACI-35, antitau antibody and morphomer tau. All this drugs are under clinical trials and have shown promising result during the preclinical trials and are now under different phases of clinical trials.

CRENEZUMAB:

It is an aloof approach for immunotherapy in which treatment to patients is given with monoclonal antibodies that perceives Aβ peptides particularly. It perceives various types of accumulated Aβ, incorporating monomeric Aβ with low proclivity,

oligomeric and fibrillar species and amyloid plaques with high partiality. This immune response mostly utilizes IgG4 as spine. It clears abundance Aβ while applying impact on microglia; it animates phagocytosis of amyloid and maintain a strategic distance from symptoms like vasogenic edema.
Clinical trials: Stage 1 trials were directed in two gatherings of individuals one in solid volunteers and other with Alzheimer’s this were the security trails in which no indications of vasogenic edema or cerebral microhemorrhage, which permitted Stage 2 in which higher measurements were utilized to accomplish higher presentation to mind than was conceivable with past immunotherapy approaches. A Stage 2 trial a dosage of 15 mg/kg every long stretch of crenezumab subcutaneous infusions, it was directed in North America and Europe in 450 individuals with mellow to direct Advertisement. ABBY and a 91- understanding biomarker think about was called Blast and in spring 2014 it got finished. ABBY missed its essential endpoints of progress on ADAS-machine gear-piece and CDR-Cry. The investigation announced that treatment and fake treatment bunches isn’t isolated on the essential endpoint of PET amyloid imaging, however reported a partition on the auxiliary endpoint of CSF Aβ.
Crenezumab is likewise being tried in a counteractive action. In a five year
contemplate which was begun in 2013, crenezumab was assessed as a major aspect of the Alzheimer Anticipation Activity and is first utilized as immunotherapy. At the season of enrolment the members in this

trial did not meet criteria for gentle subjective hindrance. This trial utilized a composite comprising of five separate intellectual tests for the essential result. A broad rundown of auxiliary results were likewise utilized, including security, time to movement to MCI, and also clinical results and liquid and imaging biomarkers. In Stage 2 trial 300 members were relied
upon to be selected and it would keep running till 2020. In February 2015, a Stage 1b think about was begun in 72 individuals with three dosages of
intravenous crenezumab and fake treatment were contrasted having mellow with direct Promotion. Dosages were not uncovered, but rather a course of 3-month of two imbuements month to month was trailed by an alternative of year open name dosing. In July 2015, crenezumab went into Stage 3, at first prodromal Promotion was examined. In January 2016, an
investigation in 750 individuals’ enrolment

with MCI or prodromal Promotion with biomarker confirmation of Aβ pathology was begun. This trial utilizes change on the CDR-SB as essential result and a scope of intellectual and useful measures as auxiliary results. In this manner was called CREAD and it utilized 233 examination areas all around and is required to keep running until 2020. In 2016 consequences
of the 72-quiet stage 1 trial, was reported. It asserted that both datasets anticipated a more grounded treatment advantage from the higher dosage of 60 mg/kg of crenezumab injected once every month for the CREAD Stage 3 contemplate, which was later on affirmed that previously mentioned measurement was assessed. On February 28, 2017, air conditioning Insusceptible reported that Genentech had chosen to begin a moment stage 3 trial of 750 members with prodromal to gentle Promotion, which is called CREAD2.

ACI-24: It is a liposomal restorative hostile to Abeta immunization fortifies a patient’s invulnerable framework to deliver antibodies that particularly focus on the oligomeric and fibrillary Aβ proteins to forestall beta amyloid plaque collection and to upgrade plaque leeway. It is presently under stage 1 or 2B. Preclinical information demonstrates a noteworthy movement in plaque decrease and memory reclamation and has an absence of neighborhood aggravation and a method of activity free of fiery Lymphocytes. ACI-24 is as of now in a stage 1/2a clinical investigation in patients with gentle to direct Promotion.

ACI-35: It fortifies invulnerable framework to deliver antibodies against the misfolded and phosphorylated pathogenic types of Tau protein which makes neurofibrillary tangles one of the real signs of Alzheimer’s ailment. It is at present under stage 1B clinical trials. In preclinical testing it gave counter acting agent reaction that was very particular to pathogenic Tau and brought about a decrease of both misfolded and phosphorylated Tau. ACI-35 is as of now in a clinical stage 1b ponder in patients with gentle to direct Alzheimer’s illness.

ANTI-TAU ANTIBODY: The anti-Tau monoclonal antibody was authorized to Genentech in 2012 and contains monoclonal adapted antibodies which is particular for obsessive Tau. This medication is at present under stage 1 clinical trials.

MORPHOMER TAU: Hinders the conglomeration and seeding procedure of misfolded proteins and advance the disaggregation of effectively framed protein totals. It is still under preclinical trials. Preclinical examinations propose lessening of neurotic Tau totals prompting memory change.

CONCLUSION:
Alzheimer’s disease poses a lot of burden on the society. Current treatments are not able to produce complete cure of the disease. Crenezumab can possibly be a standout amongst the most encouraging
treatments for this major worldwide ailment. ACI-24 is used for passive
immunotherapy for Alzheimer’s disease and specifically acting passively on Aβ aggregates. ACI-35 is an active immunotherapy for Alzheimer’s disease
targeting p-tau. Morphomer tau is a small molecule for AD treatment. Anti-tau antibody is a specific antibody for ptau. With better understanding of novel targets, drugs can be designed in future to improve
the condition and benefit the society.

REFERENCES:
i) Wischik C, Storey J.; Alzheimer’s Disease– Amyloid, Tau and beyond: Tau Aggregation Inhibitor therapy for Alzheimer’s Disease; Biochem.
Pharmacol. 2016; 88 (4): 529-539.

ii) Bateman R., Berry S.; The DIAN-TU Next Generation Alzheimer’s
prevention trial: Adaptive design and disease progression model;

Alzheimer’s and Dementia. J Alzh Asso. 2017; 13 (1): 8.

iii) Statistical data from: https://www.alz.org/documents_custom/2016-facts-and-figures.pdf.