Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

Abstract

There is no effective drug to treat Alzheimer's disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.Keywords: Alzheimer's disease; amyloid-beta; neurotrophic factors; treatment IntroductionAlzheimer's disease (AD) is an age-related, progressive and irreversible neurodegenerative disease that causes serious cognitive dysfunction. Its pathological hallmarks are extracellular deposits of amyloid-beta (Aβ) and intracellular neurofibrillary tangles, together with drastic synaptic and neuronal reduction or loss [1] . It has been estimated that AD affects 30 million people around the world [2] , and the past two decades have witnessed an explosion in research into the underlying mechanisms as well as potential therapeutic strategies. Although it was first described by German psychiatrist Alois Alzheimer in 1906, there is still no cure for AD, partly because the cellular and molecular mechanisms underlying it are far from clear. The Food and Drug Administration in the United Stateshas approved a limited range of drugs to treat AD, including acetylcholinesterase inhibitors (AChEIs) and N-methyl-Daspartate receptor (NMDAR) antagonists [3] , although their effects are merely symptomatic and memory-improvement occurs within a limited period. Donepezil, galantamine, rivastigmine and tacrine are AChEIs that prevent the breakdown of acetylcholine released from presynaptic terminals, increasing the residence time of the neurotransmitter within the synapse and thereby prolonging the duration of its interaction with postsynaptic receptors [4] . Memantine, an NMDAR antagonist, has been approved for the treatment of moderate and severe AD; it works by preventing the excitatory neurotoxicity induced by excessive glutamate [5] .Currently, no available pharmacological agents cure or reverse the progression of this devastating neurological disorder. It is therefore urgent to improve our understanding of its pathogenesis, and then develop an effective treatment strategy. This review aimed to provide insights Neurosci Bull February 1, 2013, 29(1): 111-120 112 into the design of potentially effective pharmaceutical treatments for AD by targeting two seemingly separate but tightly connected components, Aβ and neurotrophic factors (NTFs). Aβ as a Promising Target for AD TreatmentAβ is a peptide of 36-43 amino-acids produced from amyloid precursor protein (APP) through aberrant cleavage by...

Carboxypeptidase E (NF-α1): a new trophic factor in neuroprotection

“…CPE is an emerging and a promising therapeutic target for neurodegenerative diseases. Encouragingly, clinical trials have shown that neurotrophic factors are potentially effective in treating AD [32] . Thus, continued investigations into the function of CPE/NF-α1 as a new trophic factor are warranted.…”

Regulation of Autophagy in Neurodegenerative Diseases: A Brief Review on Autophagy Therapy for Neurodegenerative Diseases

“…This peptide accumulates during the course of AD and has been linked to memory impairments and dysfunctional neurons in the cortex and hippocampus. 71 Particularly, Aβ-peptide appears to be formed in autophagosomes, which also appear to contain presenilin-1 enzymes and APP that help break down APP into Aβ-peptide. Autophagy conditions may also have a substantial impact on the -peptide release into extracellular space, which leads to the development of plaques.…”

Therapeutic implication of autophagy in neurodegenerative diseases

“…However, the Aβ peptide derived from the successive splitting of amyloid precursor protein (APP) through the β-site APP cleavage enzyme 1 (BACE1) and γ-secretase also has been linked to neurodegeneration. Accumulation of this peptide has been shown to cause cognitive deficits and neuronal dysfunction in the cortex and hippocampus during AD pathogenesis ( 40 ). Particularly, Aβ may also be produced in autophagosomes, which seem to comprise APP and presenilin-1 enzymes that participate in the cleavage of APP to Aβ ( 41 ).…”

“…Furthermore, statin, a class of lipid-lowering medications, has been demonstrated to induce autophagy in astrocyte cultures through AMPK-mTOR mediated pathways, and as it has been suggested that autophagy is essential in insulin-degrading enzyme secretion, modulation of autophagy could provide a possible therapeutic approach in Aβ pathology by increasing clearance of extracellular Aβ ( 98 ). Hence, accumulation of Aβ peptide participates in the pathological condition of AD, while inhibiting Aβ production or increasing Aβ removal may be implicated in slowing the progression of AD ( 40 ). In particular, the promotion of Aβ clearance is currently considered to be an additional therapeutic approach for AD.…”