The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus), and zinc has apparently been used fairly steadily throughout Roman and modern times (for example, as the American lotion named for its zinc ore, 'Calamine'). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be 'the calcium of the twenty-first century'.

The neurobiology of zinc in health and disease

Trace elements in human physiology and pathology: zinc and metallothioneins.

The amyloid-β peptide (Aβ) is a key protein in Alzheimer’s disease (AD) pathology. We previously reported in vitro evidence suggesting that Aβ is an antimicrobial peptide. We present in vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides.

Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease

IW Hamley Chemical reviews, 2012 ACS Publications ... the γ-secretase complex and its cell surface localization, in the absence of an effect on Notch ... in the development of effective γ-secretase inhibitors is to avoid side-effects caused by ... EP2 receptor.(79) Prostaglandin E 2 is produced during inflammation due to activity by cytosolic ... Cited by 143 Related articles All 4 versions Cite Save

/pdf/the-amyloid-beta-peptide-a-chemist-s-perspective-role-in-45cfs3lkvz.pdf

The amyloid beta peptide: a chemist's perspective. Role in Alzheimer's and fibrillization.

Brain-derived neurotrophic factor is reduced in Alzheimer's disease.

A four- to fivefold overexpression of the gene for the Alzheimer beta/A4 amyloid precursor protein (APP) in individuals with Down's Syndrome (DS) appears to be responsible for the fifty year earlier onset of Alzheimer's disease (AD) pathology in DS compared to the normal population. It is therefore likely that a deregulated overexpression of the APP gene is a risk factor for the beta/A4 amyloid formation. To test this hypothesis and to get a better understanding of how APP expression is regulated, we studied the 5' control region of the human APP gene, alternative splicing of the 19 APP exons, and APP biogenesis, metabolism and function. The analysis of the APP promoter revealed its similarity with those of housekeeping genes by the presence of a GC-rich region around the transcription start site and the lack of a TATA box. Gene transfer experiments showed this GC-rich region to contain overlapping binding sites for different transcription factors whose binding is mutually excluded. An imbalance between these factors may cause APP overexpression and predispose to AD pathology. Another putative risk factor for AD is regulation of splicing of exon 7 in APP mRNA's which changes in brain during aging. This is relevant for APP processing since exon 7 codes for a Kunitz protease inhibitory domain. Investigation of further splicing adjacent to the beta/A4 exons 16 and 17 which might also interfere with APP processing led to the identification of the leukocyte-derived (L-APP) splice forms which lack exon 15. In brain this splicing occurs in activated astrocytes and microglia. The localization of APP at synaptic sites in brain suggests that APP regulation and expression are critical determinants of a potential and early impairment of central synapses. This may be the case during pathological evolution of AD and DS when beta/A4 derived from synaptic APP is converted to beta/A4 amyloid by radical generation.

Regulation and Expression of the Alzheimer's β/A4 Amyloid Protein Precursor in Health, Disease, and Down's Syndromea

The structure of the promoter of the human APP gene resembles that of housekeeping genes, with the presence of a GC-rich region and the lack of a canonical TATA box. Since analysis of the expression of the APP gene, especially at the transcriptional level, might reveal factors or elements, which influence amyloid formation in Alzheimer's disease, a 5' deletion analysis of the APP promoter was performed, leading to the identification of an activating DNA fragment (Ac), acting also on a heterologous promoter. DNaseI-footprint analysis revealed three protected regions on the Ac fragment. Further gene transfer experiments showed, that at least two elements, designated A and C, confer transcriptional activity in HeLa cells. Whereas the proximal element A is a 19bp long GC-rich DNA sequence, the distal element C is a GC-palindrome with the sequence 5'GCGGCGCCGC.

The expression of the amyloid precursor protein (APP) is regulated by two GC-elements in the promoter

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2894%2901176-1

Interaction between the zinc(II) and the heparin binding site of the Alzheimer's disease βA4 amyloid precursor protein (APP)

Specific binding of the alzheimer βA4 amyloid precursor to collagen, laminin, and heparin

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Regulation and Expression of the Alzheimer's β/A4 Amyloid Protein Precursor in Health, Disease, and Down's Syndromea

The expression of the amyloid precursor protein (APP) is regulated by two GC-elements in the promoter

Interaction between the zinc(II) and the heparin binding site of the Alzheimer's disease βA4 amyloid precursor protein (APP)

Specific binding of the alzheimer βA4 amyloid precursor to collagen, laminin, and heparin