New drug discovery for Alzheimer′s disease: Challenges and hopes

Abstract

Byline: T. Sathyanarayana Rao, K. Rao Alzheimer's disease (AD) is a common neurodegenerative disease that affects cognitive function in the elderly. It is a common dementia related to aging and a fatal neurodegenerative disease, which is on rise in both the developed and the developing countries. The disease has a complex pathology and etiology. There are no biomarkers for early detection of the disease. There are no successful drugs either to cure or to manage the disease. It has affected 4.5 million people in the United States alone in 2000 and is expected to reach about 15 million by the year 2050 in spite of all the medical advancement. Patients develop progressive cognitive decline with psychiatric and behavioral problems that impair daily living activities and also passively affect quality of life of the patient and the family. The burden of AD has an extraordinary social and economic impact on the families and on the world itself. This makes the development of potential therapies a high priority area in biomedical research. The main challenge is to choose the right biochemical target for drug discovery because of complex neuropathology of the AD brain. The large extracellular beta-amyloid (A[sz] ) plaques and tau-containing intraneuronal neurofibrillary tangles characterize AD from a histopathologic perspective.[sup] [1] However, the severity of dementia in AD is more closely related to the degree of the associated neuronal and synaptic loss. It is not known how neurons die and synapses are lost in AD.[sup] [2] Most of the evidence indicates that precursor protein (APP) processing has a central role in the AD process. The A[sz] in the form of plaques is a metabolite of the APP that forms when an alternative (beta-secretase and then gamma-secretase enzymatic pathway) is utilized for processing. A total of six mutations have been described in the APP gene, which leads to AD by influencing APP metabolism.[sup] [3] One of the leading theories is that A[sz] in plaques leads to AD because A[sz] is directly toxic to the adjacent neurons. Other theories advance the notion that neuronal death is triggered by intracellular events that occur during APP processing or by extraneuronal preplaque A[sz] oligomers. Now, AD has been understood as a more general problem with protein processing, from accumulation of intraneuronal A[sz] or extracellular, preplaque A[sz] leading to neuronal cell death. However, recently functional imaging studies implied that functional decline in humans can occur separately from both neuronal loss and neurofibrillary tangles. A[sz] , a 39-43 aminoacid peptide derived from APP is the major component of senile plaques observed in AD. Evidences implicate a central role for A[sz] in the pathophysiology of AD. Av40 is the dominant species in human cerebrospinal fluid, accounting for approximately 90% of total A under normal conditions. There is a disease-specific increase in A[sz] 40 brain tissue levels compared with the A[sz] 42 change observed both in the aged and in the AD brain. It is now speculated that A[sz] pathological significance is also known to be associated with a-synuclein aggregation, a protein implicated in Parkinson's disease. A[sz] is a self-aggregating protein and the conformational transition from unfolded state to a beta sheet-rich conformation leads to deposition of protein aggregates. Although A[sz] deposits are primarily extracellular, studies have demonstrated an intraneuronal accumulation of A[sz] in AD-vulnerable regions. It is said that the amyloid is deposited first in the neuron and later in the extracellular space. Thus, neurodegeneration (ND) includes complex pathology and etiology. No animal model completely reflects human ND seen in the brain. The major challenges are how to choose the best neuronutraceuticals for clinical trials, what kind of preclinical study design is required and whether we can formulate a synthetic or modification of the natural compound best suited for the brain. …