Alzheimer’s Disease: Novel Targets and Drugs

Introduction

Alzheimer’s disease (AD) is a common age-related dementia, distinct from vascular dementia, associated with brain shrinkage and localised loss of neurons, mainly in the hippocampus and basal forebrain. The main pathological features of AD comprise amyloid plaques, neurofibrillary tangles and a major loss of cholinergic neurons, particularly in the basal forebrain. Enormous effort is now being devoted to developing drugs that slow neurodegeneration in Alzheimer’s disease (AD), although insights into AD genetics and molecular pathogenesis only arose in the last 15 years. Acetylcholinesterase inhibitors that temporarily slow loss of cognitive function remain the only approved AD drugs. Discovery of mutations in three genes leading to severe early onset AD was critical in focusing attention on the role of amyloid peptides (Aβ) in neuronal cell death, and enhanced understanding of the biology of these peptides has led to an array of mechanism-based drug discovery strategies. These include inhibitors for Aβ-generating proteases, agents that prevent or reverse Aβ oligomerization, immunotherapies to reduce Aβ in brain and plasma, and drugs to modulate cholesterol-mediated effects on Aβ transport. Strategies are also underway to minimize toxic effects of Aβ fibrils on neurons, and these include antioxidants, blockers of glutamate-mediated excitotoxicity, and modulators of inflammatory responses within the brain. Although several approaches involve new agents for recently discovered targets, many are based on new applications of existing drugs such as statins and nonsteroidal anti-inflammatory drugs. Discovery of abnormally phosphorylated protein in neurofibrillary tangles in AD brain has led to strategies for identifying selective inhibitors of τ kinases and central nervous system/brain-permeable drugs that help maintain microtubule integrity.

NOVEL THERAPEUTIC TARGETS AND DRUGS FOR ALZHEIMER’S DISEASE

1. Inhibition of β- and γ-Secretase Activities:

   The β-secretase (BACE; β -site APP-cleaving enzyme), aka Asp2 or memapsin 2, was initially discovered through an expression cloning strategy to identify genes that altered Aβ production. The novel BACE proteases most closely resemble the pepsins. Although BACE activity may not be rate limiting, it is absolutely required for Aβ production. Although such large peptides are not likely to be developed as drugs, they are providing lead structures for ongoing design of selective, brain-permeable, small-molecule inhibitors

2. Clearance of Aβ Peptides:-

Although the large Aβ aggregates present in plaques were initially regarded as the culprits responsible for neurodegeneration, recent biophysical studies on Aβ fibrils indicate that early protofibrillar forms of the peptide may initiate the cell death cascades. These findings have raised questions about whether AD, particularly the late onset sporadic form, results from overproduction of Aβ or from a failure to prevent protofibril formation or to clear the peptide rapidly enough to prevent fibrillization

3. Reducing the Cellular Toxicity of Aβ:-

An important therapeutic strategy is aimed at reducing the toxic cellular events that occur with Aβ accumulation in the vicinity of neurons, particularly those due to inflammatory cascades and free-radical generation. Recent observations on astrocyte activation as part of a neuro-inflammatory cascade led to the identification of a novel death associated protein kinase as a mediator of diverse apoptotic signals. Derivatives of 3-amino pyridazine appear to be selective inhibitors of this kinase, leading to the possibility that Aβ activation of neuro-inflammatory responses in astrocytes can be modulated with this novel class of agents

4. Neurofibrillary targets:-

τ is predominantly a neuronal protein encoded in a single gene, with six splice variants expressed in adult brain, primarily in axons. Depending on the splicing of exon 10, the carboxy terminal of the expressed τ contains either three or four MT-binding regions composed of repeats of a highly conserved 18 amino acid motif (3R- τ or 4R- τ). The ratio of 3R- τ to 4R- τ is ~1.0 in human brain. The 4R- τ forms bind MTs with higher affinity and are more efficient in promoting MT assembly. Many of the more than 20 pathogenic mutations in τ lead to an increase in 4R- τ versus 3R- τ, although the mechanisms by which this leads to neuronal dysfunction are not known. In AD, the neurofibrillary pathology is not due to mutations in the τ gene but rather to some cellular cascade that results in abnormal phosphorylation of τ proteins that causes them to assemble into filaments. These filaments occupy space in the cytosol and also prevent normal τ regulation of MT structure and activities such as axonal transport. Identification of the kinases involved in τ phosphorylation is being actively pursued, as such enzymes are potential therapeutic targets.

CONCLUSION

The remarkable pace of discoveries over the past decade has led to an impressive array of mechanism-based approaches to therapeutic interventions. Advances in understanding many of the molecular events leading to neurodegeneration and the genetics of early onset AD have uncovered totally new drug targets. Identification of the secretase families and their protein partners is certainly a case in point. Although new classes of drugs are now being developed to modulate the activities of recently discovered targets, it is quite interesting that many of the therapeutic strategies under intensive investigation involve the use of older pharmacological agents. The statins, NSAIDs, antioxidants, and metal chelators certainly show promise as disease-modifying agents that may become part of multidrug regimens to slow clinical progression of the disease. At the same time, the work with such agents in the context of AD pathogenesis has provided unanticipated insights into the pharmacological activities of these well known drugs. For example, efforts to understand the mechanism for the beneficial effects of statins have led to several discoveries about the trafficking of cholesterol-containing particles into and out of the CNS. The synergy occurring between basic cell and molecular studies in AD models and efforts to come up with therapeutic agents, either old or new, is also driving the development of better strategies for future clinical trials. There is a great need for reliable diagnostic indicators that permit patient identification prior to extensive cell death, if drugs for primary prevention are to become a reality. Most clinical trials are conducted in patients with moderate AD, and the criteria for effectiveness currently involve standard assessments of cognitive and global functioning over time. New brain imaging technology for early detection and, especially for the monitoring of disease progression under experimental drug regimens, appears to be on the horizon and will greatly improve the entire drug discovery enterprise directed against this devastating disease.

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By- Valavalkar Vidula V S
M. Pharm., BITS-Pilani