Targeting Transition Metals for Neuroprotection in Alzheimer’s Disease

doi:10.1016/B978-0-12-803690-7.00010-7

Neuroprotection in Alzheimer's Disease

2017, Pages 193-215

https://doi.org/10.1016/B978-0-12-803690-7.00010-7 Get rights and content

Abstract

Alzheimer’s disease (AD) is a prevalent, devastating, and therapeutically intractable disease of the elderly. Amyloid beta and tau proteins are the main drivers of neurodegeneration in this disease, but drugs targeting these proteins have not been effective in clinical trial so far. The transition metals, iron, copper, and zinc, are also implicated in Alzheimer’s pathogenesis and are alternate drug targets. Here we outline the pathological changes to these transition metals in AD, and discuss the rational and recent attempts to therapeutically target these for disease modification in AD.

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Metal ion coordination in peptide fragments of neurotrophins: A crucial step for understanding the role and signaling of these proteins in the brain
2021, Coordination Chemistry Reviews
Citation Excerpt :
The stability constant value of each species is the only parameter that provides the affinity of a metal ion for a ligand on a quantitative basis; in addition, this parameter makes it possible to obtain the distribution of all existing species over a given pH interval and to compare the affinity of a metal ion for the ligand of interest with that of other ligands. This is of crucial importance in order to improve the picture of the real situation and may help designing synthetic molecules for therapeutic use [104–106]. Though it is still being debated [104] whether metal-protein interactions are under kinetic [107] or thermodynamic control [108], determining the thermodynamic parameters of the steps thought to be involved in the cascade of naturally occurring events may be a major step for the understanding of the entire process.
Some metal ions of the d-block are necessary for the proper growth, functioning and maintenance of the central nervous system. In particular, copper and zinc ions have emerged as effective non-structural intracellular mediator of cell signaling. The high zinc and copper levels in the synaptic cleft are associated with the shaping of synaptic plasticity and, thus, with learning and memory formation processes. Recent findings identify neurotrophins (NTs) as potential targets of metal ions in the kinase signaling networks of neuronal tissues. Neurotrophins are a class of proteins crucial for the growth and preservation of the central nervous system as they preside over processes/functions like neuroplasticity, memory and learning. A deficit in the expression and activity of these proteins is associated to many neurodegenerative pathologies as Alzheimer and Parkinson’s diseases.
Knowing the coordination chemistry of metal ions to NTs is an essential step to identify the basis of NTs/metal ions physiology in learning and memory formation as well as the factors that trigger memory impairment in neurodegeneration, NTs conformations, NTs chemical properties and their biological functions. Unfortunately, characterizing the metal ion coordination of the whole protein is hardly feasible if not impossible. Thus, the design and synthesis of peptides able to mimic the binding and functional sites of proteins may be a viable strategy to explore protein activity and conformational features, metal ion binding as well as to design new molecules for neurodegenerative disorders.

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Chapter 10 - Targeting Transition Metals for Neuroprotection in Alzheimer’s Disease

Abstract