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Pharmacotherapeutic targets in Alzheimer's disease.

Biran Y, Masters CL, Barnham KJ, Bush AI, Adlard PA - J. Cell. Mol. Med. (2008)

Bottom Line: However, numerous compounds are currently undergoing pre-clinical and clinical evaluations.These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated tau-protein, the amyloid-beta(Abeta) peptide and metal ion dyshomeostasis--all of which are involved in the development and progression of AD.We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category.

View Article: PubMed Central - PubMed

Affiliation: The Oxidation Biology Laboratory, The Mental Health Research Institute, Parkville, Victoria, Australia.

ABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated tau-protein, the amyloid-beta(Abeta) peptide and metal ion dyshomeostasis--all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category.

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Related in: MedlinePlus

Copper binding domains on APP. APP contains two high-affinity copper binding domains: one on its N-terminus and the other on the Aβ sequence. Highlighted in red are the copper binding ligands in the CuBD and in the Aβ1–42 sequence. Abbreviations: Aβ (amyloid-β); APP (amyloid precursor protein); CuBD (copper binding domains); TM (trans-membrane).
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fig03: Copper binding domains on APP. APP contains two high-affinity copper binding domains: one on its N-terminus and the other on the Aβ sequence. Highlighted in red are the copper binding ligands in the CuBD and in the Aβ1–42 sequence. Abbreviations: Aβ (amyloid-β); APP (amyloid precursor protein); CuBD (copper binding domains); TM (trans-membrane).

Mentions: It has been demonstrated that APP contains putative zinc and copper-binding domains (CuBD) both in its ectodomain and in its Aβ sequence (see Fig. 3). Little is known about the APP Zn-binding domain; however, it has been established that its CuBD consists of a tyrosine (Tyr168), a methionine (Met170) and two histidine (His147, 151) residues that are able to coordinate Cu2+ and reduce it to Cu+[244]. The similarities between the CuBD on APP and Cu chaperone proteins suggest that APP may play a role in metal homeostasis [245]. This notion has recently gained support from findings that the translation of APP mRNA is governed by the binding of an iron-regulatory element to its 5′-untranslated region such that in an Fe-enriched environment APP translation is up-regulated, whereas it is down-regulated in response to an Fe-deficient milieu [246, 247]. Moreover, increasing Cu levels in vitro can shift APP processing towards the non-amyloidogenic pathway and result in decreased Aβ production [222–225]. This may result from an increase in GSK-3β phosphorylation, which activates phosphatidylinositol-3-kinase (PI3K) to result in the secretion of MMPs that can degrade Aβ[225]. In addition, genetically modified animal models of AD provide vital clues as to the affects of APP and Aβ on metal-ions and vice versa. Tg2576 mice that over-express the Swedish double mutant APP695 (K-670-N and M-671-L) exhibit AD-related behavioural and cognitive changes (memory and spatial learning impairments) [248] and AD-related pathology (substantially elevated levels of full-length APP, CTFs and cerebral extracellular Aβ) [249]. However, their cerebral Cu (but not Fe) levels are significantly reduced [224, 250]. C100 mice over-express Aβ and the C-terminal of APP, yet have significantly lower levels of both Cu and Fe in the brain [250]. Conversely, APP (and APLP2) knockout mice have raised brain and liver Cu levels [251] and develop reactive cerebral gliosis and locomotor-behavioural changes with age [252]. These studies all suggest a role for APP in metal homeostasis. As a further demonstration that metal homeostasis is important in the pathogenesis of AD, when APPswe/PS1P-264-L-expressing mice, which also have ∼15% lower brain Cu levels compared to non-transgenic controls, are crossed with TxJ ‘toxic milk’ mice (that have a mutated ATPase7b transporter and a consequent elevation in Cu levels), the resulting progeny have markedly reduced AP load and Aβ levels [224]. Similarly, increasing dietary copper intake in APP23 mice (carrying the Swedish mutation of human APP751, regulated by the murine Thy-1.2 promoter [253]) resulted in reduced Aβ levels and a prolonged lifespan [222]. Conversely, increasing dietary Cu intake in normal rabbits resulted in elevated Aβ levels and impaired learning [134, 254]. Thus, metal homeostasis appears to be intimately involved in Aβ metabolism.


Pharmacotherapeutic targets in Alzheimer's disease.

Biran Y, Masters CL, Barnham KJ, Bush AI, Adlard PA - J. Cell. Mol. Med. (2008)

Copper binding domains on APP. APP contains two high-affinity copper binding domains: one on its N-terminus and the other on the Aβ sequence. Highlighted in red are the copper binding ligands in the CuBD and in the Aβ1–42 sequence. Abbreviations: Aβ (amyloid-β); APP (amyloid precursor protein); CuBD (copper binding domains); TM (trans-membrane).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3823037&req=5

fig03: Copper binding domains on APP. APP contains two high-affinity copper binding domains: one on its N-terminus and the other on the Aβ sequence. Highlighted in red are the copper binding ligands in the CuBD and in the Aβ1–42 sequence. Abbreviations: Aβ (amyloid-β); APP (amyloid precursor protein); CuBD (copper binding domains); TM (trans-membrane).
Mentions: It has been demonstrated that APP contains putative zinc and copper-binding domains (CuBD) both in its ectodomain and in its Aβ sequence (see Fig. 3). Little is known about the APP Zn-binding domain; however, it has been established that its CuBD consists of a tyrosine (Tyr168), a methionine (Met170) and two histidine (His147, 151) residues that are able to coordinate Cu2+ and reduce it to Cu+[244]. The similarities between the CuBD on APP and Cu chaperone proteins suggest that APP may play a role in metal homeostasis [245]. This notion has recently gained support from findings that the translation of APP mRNA is governed by the binding of an iron-regulatory element to its 5′-untranslated region such that in an Fe-enriched environment APP translation is up-regulated, whereas it is down-regulated in response to an Fe-deficient milieu [246, 247]. Moreover, increasing Cu levels in vitro can shift APP processing towards the non-amyloidogenic pathway and result in decreased Aβ production [222–225]. This may result from an increase in GSK-3β phosphorylation, which activates phosphatidylinositol-3-kinase (PI3K) to result in the secretion of MMPs that can degrade Aβ[225]. In addition, genetically modified animal models of AD provide vital clues as to the affects of APP and Aβ on metal-ions and vice versa. Tg2576 mice that over-express the Swedish double mutant APP695 (K-670-N and M-671-L) exhibit AD-related behavioural and cognitive changes (memory and spatial learning impairments) [248] and AD-related pathology (substantially elevated levels of full-length APP, CTFs and cerebral extracellular Aβ) [249]. However, their cerebral Cu (but not Fe) levels are significantly reduced [224, 250]. C100 mice over-express Aβ and the C-terminal of APP, yet have significantly lower levels of both Cu and Fe in the brain [250]. Conversely, APP (and APLP2) knockout mice have raised brain and liver Cu levels [251] and develop reactive cerebral gliosis and locomotor-behavioural changes with age [252]. These studies all suggest a role for APP in metal homeostasis. As a further demonstration that metal homeostasis is important in the pathogenesis of AD, when APPswe/PS1P-264-L-expressing mice, which also have ∼15% lower brain Cu levels compared to non-transgenic controls, are crossed with TxJ ‘toxic milk’ mice (that have a mutated ATPase7b transporter and a consequent elevation in Cu levels), the resulting progeny have markedly reduced AP load and Aβ levels [224]. Similarly, increasing dietary copper intake in APP23 mice (carrying the Swedish mutation of human APP751, regulated by the murine Thy-1.2 promoter [253]) resulted in reduced Aβ levels and a prolonged lifespan [222]. Conversely, increasing dietary Cu intake in normal rabbits resulted in elevated Aβ levels and impaired learning [134, 254]. Thus, metal homeostasis appears to be intimately involved in Aβ metabolism.

Bottom Line: However, numerous compounds are currently undergoing pre-clinical and clinical evaluations.These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated tau-protein, the amyloid-beta(Abeta) peptide and metal ion dyshomeostasis--all of which are involved in the development and progression of AD.We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category.

View Article: PubMed Central - PubMed

Affiliation: The Oxidation Biology Laboratory, The Mental Health Research Institute, Parkville, Victoria, Australia.

ABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated tau-protein, the amyloid-beta(Abeta) peptide and metal ion dyshomeostasis--all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category.

Show MeSH
Related in: MedlinePlus