Kyiv3

Kyiv's Lithuanian Period (1266-1764)

(To summarise my first Kyiv1 post [1]: in A.D. 1054, the polity called Kyivan-Rus stretched from the White Sea and the borders of  Finland to the Black Sea and the borders of Byzantium [2], while neither the town nor the duchy of Moscow existed.  In my second blog-post (Kyiv2) on the history of Ukraine [3], I followed the fate of Novgorod in the northern part of Kyivan-Rus as it became vassal first to the Mongolian Golden Horde, then fell progressively under the growing power of Moscow, up to the chaotic reign of Ivan the Terrible who died in 1588.)

Meanwhile, the western and southern parts of Kyivan-Rus were exposed to the growing power of Lithuania, which felt that it should, ethnically and logically, inherit the old territory of Scandinavian Rus. Whether that  belief was justified or not, it seems that Lithuania's approach to empire was distinctly more consensual than that of the other contemporary players on the checkers-board of Europe: the crusading Livonian and Teutonic Knights (to their west and north), the Mongols (to their south) and the Muscovites to their east. 

Thus, the independent and staunchly democratic city-state of Pskov, in the north-west corner of modern Russia, under attack from the Teutonic and Livonian Knights, in 1266 elected a Lithuanian prince (Daumantas) as their military leader, subject to the Veche or parliament. He fortified Pskov so successfully that the town withstood all attacks till 1510, when it was forcefully merged into the duchy of Moscow by the moving of hundreds of families. (As mentioned in Kyiv 2, also in Novgorod there was a significant minority that would have preferred Lithuanian rule to that of Moscow.)

In 1321, the Lithuanian duke Gediminas captured Kiev, sending Kyiv's last Rurikid ruler into exile. Forty years later (in 1362) the Lithuanians routed the the Golden Horde at the battle of Blue Waters on the Southern Bug. The Duke at that time was Algirdas, who was ably supported by his co-operative and loyal brother Kęstutis, who busily defended the western and northern borders of Lithuania against Poland and the Teutonic Knights respectively. 

Sandwiched between Catholic Poland to the west and Orthodox Russia to the east, the Dukes of Lithuania used their paganism as a diplomatic tool, alternately flirting with one, in order to alarm the other. Algirdas married twice, both times to Muscovite princesses, having 8 children by the first and 13 by the second. Again illustrating a diplomatic approach to politics, one of his sons (Prince Andrew) was elected as Prince of Pskov. 

Smolensk was attacked in 1395, and in 1403, but in 1404 it opened its gates voluntarily to the Lithuanians. 

In the generation after Algirdas, the flirting, this time with Catholic Poland, went a lot further than those two Muscovite marriages.  The empire of Poland-Hungary had found itself without a king when Louis of Anjou died in 1382 leaving only two daughters, Mary and Hedwig (Jadwiga). Mary was betrothed to Sigismund of Luxembourg, with Hungary as her dowery, while Hedwig was betrothed to an Austrian Habsburg. But a majority of the Polish lords thought they would do better if Poland were allied to Lithuania rather than Austria, and suggested Grand Duke Jogaila of Lithuania as Queen Hedwig's husband; provided he espouse also Catholicism. They were married in 1386, and Jogaila became King Władysław II of Poland (by marriage) while remaining Grand Duke of Lithuania.. This union of the two states was formalised, in 1569, by the Union of Lublin which created the enormous Polish–Lithuanian Commonwealth. 

The term Ukraine appears in the fifteenth century. It apparently means borderland, and describes the south east corner of Lithuania where it bordered the Islamic Ottoman territory of Crimea and south the Black Sea, and the Duchy of Moscow to the east. The political and geographic situation favoured the development of a semi-independent, semi-nomadic, multiracial, somewhat militaristic, Orthodox and Slavic-speaking culture, identified as Cossack.

The hundred years from 1555 to 1655 saw the apogee of the Polish–Lithuanian Commonwealth. In 1610 Polish cavalry defeated Russian forces, captured Moscow and took the Tsar (Vasili IV) back to Warsaw in a cage; where he was humiliated and murdered. In 1620 war with the Ottomans lost some territory to the south, and in 1626-1629 war with Sweden lost more territory to the north. Various factions arose, pro-French, pro-Habsburg. The crown seldom passed from father to son, and was often chosen by a process of election (by the nobles). Nevertheless the monarch hankered after absolutism (as was the fashion of the times).  In 1648, attempts to impose Catholicism angered Ukrainian Cossacks and led them to revolt. (It also angered protestant Sweden, and in 1655 lost Poland its control over Prussia, heralding Poland's decline as a European power.)

        When the Cossack leader Bohdan Khmelnytsky marched into Kyiv in 1648, he was greeted with joy as a liberator from the Polish yoke. But after 6 years of war with Poland, during which he was repeatedly let down by the Crimean Tartars, Khmelnytsky started negotiations with Moscow. A treaty was concluded in April 1654 in Moscow by which Cossack Zaporozhia became an autonomous Hetmanate within the Russian state (Zaporozhia means 'beyond the rapids', presumably the area down-stream, as Dnipro is north of Zaporozhia). Ukraine retained that status until Catherine II (the 'Great') of Russia abolished the Hetmanate in 1764. 

(See my continuation post Kyiv4)

References 

(General reference:https://en.wikipedia.org/wiki/Category:History_of_Ukraine)

[1] https://occidentis.blogspot.com/2023/03/kyiv-1.html   

[2] https://en.wikipedia.org/wiki/Kievan_Rus%27#/media/

File:Location_of_Kyivan_Rus.png

[3] https://occidentis.blogspot.com/2023/03/kiev-2.html 

Kiev2

 'The Chronicle of Novgorod'

From 862 - 1470 the history of European Russia is essentially the same as the history of Ukraine. Prestige and power moved north to Novgorod when the Golden Horde stormed in from Mongolia. Then moved eastwards to Vladimir-Suzdal (and eventually to the nearby Moscow).

As discussed in Kyiv 1 [1], the origin of Novgorod and Kyiv are closely intertwined. Novgorod was founded 862 by Swedish Varangians under the leadership of Rurik. Kyiv was taken over by Rurik's kinsmen in 880, and the two cities forming the binary foci of a successful polity that grew till it reached from the Black Sea to the White Sea. During the rule of the great princes (Sviatoslav, 943–972; Vladimir the Great, 980–1015; Yaroslav the Wise; 1019–1054) the cities co-operated, and shared in the benefits; thus they both adopted Byzantine Christianity and the Glagolitic script under Vladimir the Great, and the Book of Laws under Yaroslav the Wise. But under lesser leadership there was a rivalry, for example between princely descendants of Yaroslav, because the one who held Kyiv was traditionally awarded the title 'Great Prince' of the Kyiv-Rus federation.  Much destructive internecine warfare ensued, (though there was a brief respite under Rostyslav Mstyslavych of Smolensk who achieved unity without warfare). 

However, in 1169 a different type of coalition mustered to attack Kiev under the leadership of Andrey Bogolyubsky, for it was led by princes from further east than present-day Moscow, in fact from Vladimir-Suzdal, and contained non-Rus elements such as the Polovtsians. The collapse of Kyiv did not lead to the installation of a new Great Prince of Kyiv as was usual when the city was defeated, but instead to a three-day massacre and the pillaging of its most sacred relics. It was as though Kyiv fell to 'foreigners'.  In 1169 Novgorod withstood attack by Andrey Bogolyubsky, and 4 years later Novgorod helped the Ukrainians to defeat a second attack by Andrey Bogolyubsky.  However Kyiv was fated to fall again, even more drastically, to the Golden Horde in 1240.

Novgorod, (that is to say Novgorod the Great, 147 miles south of St. Petersburg, not Nizhney Novgorod, 260 miles east of Moscow), Novgorod  managed to avoid a similar fate, realising when to humble itself and pay tribute. The story of Novgorod is told in a fascinating document called the "Chronicle of Novgorod" (available online in Robert Mitchell's 1914 translation into English [2]). 

Novgorod in the 9th - 15th centuries developed as a very republican town. The Boyars and burgers were frequently asking their elected officers (Prince, burgomaster, bishop) to leave, often after less than a year in office, occasionally after 'a few weeks'.  

In 1238 the 17 year old Alexander Nevsky, of royal descent, but younger son of a younger son, was asked to go to Novgorod to lead the army against Scandinavian attacks from the north. It happened thus. Yuri Vsevolodovich was Grand Prince of Vladimir-Suzdal, 600 miles to the east, which had replaced the defeated Kyiv as the 'high seat' of Kyivan-Rus. But in that same year Yuri was killed in battle with the Mongols, whereupon his younger brother (Yaroslav Vsevolodovich), paying due homage to the victorious Golden Horde, requested of their leader that he (Yaroslav) take his dead brother's place, and was granted it.  As Grand Prince he assigned his younger son (Alexander) as prince of Novgorod.   

In 1240 Alexander, tall and charismatic, scored a significant victory on the banks of the river Neva (hence the epithet 'Nevsky'). Whereupon, the Boyar aristocrats asked him to leave the city. The city requested the older brother Andrey as a replacement, but the citizens did not take to him and pressed (in 1241) for the return of Alexander to meet another challenge, this time from the west in the form of the Teutonic and Livonian Knights. The joint forces of the two brothers defeated  the knights in April 1242 in the celebrated 'Battle on the ice'. (Filmed, in black and white, by Eisenstein in 1938.). 

The Gran Kahn, in Karakorum (Mongolia), was quite happy to employ local leaders as long as they paid him homage, and tax. The ageing Yaroslav Vsevolodovich was asked in 1245 to make the 3,000 mile trip from Vladimir to Karakorum, but died en route. So, in 1248 the two brothers were summoned to Karakorum, to meet the Grand Kahn, and were assigned, Andrey to the high seat of Vladimir and Alexander to the erstwhile high seat of Kiev. 

In 1251, on the death of Batu Kahn and the elevation of a new Kahn, all the Russian vassal princes were required to pay homage in person. Alexander complied but Andrey did not. However, that was a serious miscalculation; the Golden Horde was too powerful to flout in this way. Andrey had to flee to Sweden, whereupon Alexander was given the Grand Duchy of Vladimir, becoming head of all 'Russia'. He was constant in his loyalty to the Mongol overlords, and once had to lead an army against his own Novgorod to teach them to pay their taxes. Nevertheless, the Russian-Ukrainian people loved him and, after his death, his memory lived on and worked miracles; he was canonised in 1547.  

Alexander Nevsky, as Grand Duke of Vladimir-Suzdal, founded the Dukedom of Moscow in 1263 for his son Daniel. Daniel's son Yuri married the sister of the Golden Horde's new Kahn, which greatly enhanced the status of the little town of Moscow. By 1320 it had outgrown its parent. Growth continued under the rule of 3 successive generations of Rurik princes : 

● Ivan III ('the great', 1462 - 1505) who conquered Novgorod, and faced down the Golden Horde at the Great Stand in 1479. 

● Vasili III (1505-1533) who re-took Smolensk off the Lithuanians, and expanded down to the Dnieper , 

● Ivan IV ('the terrible', 1533–1547, 1547-1588 as Tsar) who expanded Moscow's power into Siberia, but wrecked havoc in European Russia with his uncontrolled psychopathology. 

The conquest of Novgorod

In 1471 Novgorod faced a dilemma resembling to some degree that of present day Ukraine [3]. Citizens recognised that survival required them to ally themselves either with the Grand Duchy of Moscow, their large neighbour to the east, or with the expanding Grand Duchy of Lithuania-Poland to their west. The ordinary citizens preferred the Orthodox and more familiar Moscow; the aristocratic Boyars preferred Catholic Lithuania. When Ivan III heard that the widow of a Novgorod Boyar (Marpha Boretskaya) had negotiated an agreement of protection with Kasimir IV of Lithuania-Poland he decided to attack. Kasimir IV faltered and the Novgorod home guard were totally destroyed just outside their city. The helpless citizens opened their gates to Ivan III. At first he merely fined the pro-Lithuanian Boyars, but over the next 8 years he dismantled the 'independence' of Novgorod, symbolically removing their 'parliamentary bell' and with it their ability to hold a parliament (or veche) and their cherished democracy [3].

Conclusions

The Swedish element, most strongly represented in democratic and republican Novgorod, lasted 750 years, but was defeated by the unitary and progressively autocratic power of Moscow. 

The Mongol element in the form of the Golden Horde, came and went, surviving as the supreme military power only for 200 years (1260-1458). Originally a limb of the Grand Kahn, it became autonomous in 1260, adopted Islam in 1313, and was demoted to 'Great Horde' in 1458. Genetically their contribution may have lasted longer.

There are doubtless some lessons to learn concerning when to submit and when to resist, and about relying on dilatory allies.  Also lessons about the efficacy (or otherwise) of icons and crosses. But these are subtle and complex matters, and each of us has to make their own assessment..

(But the story continues in Kyiv3 )

References:

[1] https://occidentis.blogspot.com/2023/03/kyiv-1.html 

[2] http://faculty.washington.edu/dwaugh/rus/texts/MF1914.pdf 

[3] https://russia.rin.ru/guides_e/6875.html 

Handshakes

How many Handshakes?

    As I sat in meeting this morning I looked around. We were ten people. I reflected that last week we were only three people, though it was an excellent meeting in all respects.  At the end, lacking an elder, we had all shaken hands with each other. 

    Today there were ten of us. The age-old problem came to mind, of how many handshakes would be involved this time if we all shook hands with each other. (I remembered the question from schooldays some 65 years ago). 

    But, with a gratifying flash of insight, the answer came to me; there would have to be 45 handshakes to be complete. The clue came from our unusually small meeting of the previous week. Three people each shook two hands making six greetings. But each shake met two of those six greetings. Answer = three. 

    I could put it this way. For n people, there would be:
                 n x (n-1)/2 
shakes. So for 10 people each greeting 9 others (as you do not greet yourself), so 90 greeting; but only 45 shakes.

Number of people (n)        Greetings            Shakes

        1                                    0                           0
        2                                    2                           1
        3                                    6                           3
        4                                   12                          6
        5                                   20                        10

    I am pretty sure I am right. But concede that it does not amount to 'Ministry'. Nor 'Afterwords', really. Perhaps I should keep it for the monthly newsletter.

       

 

Kyiv1

 Kyiv 1

Kyiv lies in a gentle bend of the river Dnipro (or Dnieper), on the hilly west bank, roughly half way between the Baltic and the Black sea. It has a long and important history, allegedly going back to a Slavic or Turkic foundation in A.D. 482, though various people undoubtedly lived there for 25 centuries before that. However, in A.D. 880 Kyiv fell to the Swedish Varangians (Vikings) and formed, for the next 360 years, a flourishing economic, military and cultural centre on that important trade route between Scandinavia and Byzantium.  

Around the time that the Danish Vikings started raiding the coasts of England, and pressing up the navigable rivers (overwintering in London in A.D. 871), and the Norwegian Vikings sailed out across the Atlantic to harry the west coast of Scotland, Ireland, France and Italy, and eventually to colonise Iceland (A.D. 874), the Swedish Varangians pushed eastwards across the Baltic and southwards up the Neva and Volkov rivers to the position of present day Novgorod. From there, some travelled east to the headwaters of the Volga, whence to the Islamic countries of the middle east, while others portaged to the headwaters of the Dnipro near Smolensk (founded A.D. 863) and, via the Black sea, to Constantinople.  It is said that a Varangian nobleman called Rurik founded Novgorod in A.D. 862, and started a royal dynasty that lasted till the Romanovs (A.D. 1598).

In A.D. 882 Oleg of Novgorod captured Kyiv, probably off fellow Vikings. Thus began the Golden age of Kyiv, the wealthy and favoured capital of a polity known as  Kyivan Rus. Under the reigns of 3 great Rurik Princes the state prospered,  expanded, converted to Christianity, acquired an alphabet, and a book of laws. And undoubtedly assimilated wholesale with the pre-existing Slavic population. Thus: under Sviatoslav (943–972) the state expanded south against the Khazars, then Vladimir the Great (980–1015) introduced Christianity, by example (988) and with it the Glagolitic (c.f. Cyrillic [1]) alphabet. Under Yaroslav the Wise (1019–1054) the state reached from the White sea in the north to the Black Sea in the south. 

Then decline began, with fratricidal successions, and internecine warfare between neighbouring cities, and states. As Byzantium declined, so did the economic value of the trade passing up and down the Dnipro. Power shifted from Kyiv to Novgorod. In 1169 Kyiv was sacked by fellow Rus; and in 1240 it fell to the Mongols in the form of The Golden Horde under the leadership of Batu Kahn.[2]

However, that was not the end of history as far as Kyiv and the Rus were concerned. (Look out for the proposed Kyiv2.)

Footnotes:

[1] Cyril and his older brother Methodius translated (c. A.D. 850) parts of the Bible into Slavonic to help them bring Christianity to the Byzantine Bulgars. For this, they modified the Greek alphabet to accommodate the phonemes important to the Slav languages. The Volga Bulgars adopted Islam and offered it to Vladimir of Kyiv, but he said the Varangians could not give up alcohol and so chose Christianity. 

[2] It is said that the Mongol commander offered terms, but his envoys were murdered and thrown over the walls, whereupon the Mongols attacked, the walls were breached, and 95% of the population executed. Novgorod paid tribute and was spared.

Memory and Attention

 Strange things do happen to me these days. Is it my memory?

A couple of days ago I found a dirty wineglass in the refrigerator. And, just now, I turned to pick up the little tray that lies on top of the microwave and was surprised when the microwave door popped open. The mystery was very soon solved. Clearly, my right hand had taken the initiative when it failed to get timely instructions from the brain. 

But is it memory that is failing in these cases? I think not. I suggest it is a failure of attention, a failure properly to cogitate about the activity one is engaged in. 

"One can neither remember, nor forget, what one was unconscious of in the first place."

Labour's five missions

What are, and what should be, Labour's five missions?

(Yestersay (23rd February) Keir Starmer announced the five missions that would characterise his government, if elected. Here I comment.)

Dear Team-at-Labour-Headquarters,

    Those are five admirable objectives, so far as they go. But it strikes me that they are likely very similar to the five objectives of the Conservative party. 

1. Secure the highest sustained growth in the G7

How? Not by cutting taxes, surely?  nearly all voices clamour for growth. Yet I do not seek growth, if it means more-of-the-same, more concrete, more motor cars). Perhaps we should aim for 'productivity' gains (which benefits everyone), and better distribution of wealth (which would benefit nearly everyone). 

2. Build an NHS fit for the future.

Even an NHS of the past would be quite good. We should try to re-establish morale, certainly, but also cap spending on e.g. expensive operations and expensive medicines, else the image of a 'bottom-less pit' looms. We suggest (again) the 'health-penny' on income-tax.

3. Make Britain’s streets safe.

I suppose again the task is to try to re-establish morale, and public confidence. Do we need to think seriously about management training? Quality circles? The 'Copper-penny' on tax?

4. Break down the barriers to opportunity at every stage.

Which barriers? And how? (You cannot make people intelligent and innovative by sending them to Oxford.) The Tory idea is competition and laissez faire; what is Labour's idea? Apprenticships?

5. Make Britain a clean energy superpower.

Clean – yes! But Superpower? Citizens are happier (more content) in Finland (7.82) and Denmark (7.64) than in any of the G10 "superpowers". Look at the Happiness indices of the G10.

(https://www.theglobaleconomy.com/rankings/happiness/G10/)

Switzerland 7.51

Netherlands 7.41

Sweden 7.38

Canada 7.03

Germany 7.03

USA 6.98

UK 6.94

Belgium 6.8

France 6.69

Italy 6.47

Japan 6.04

I would like Britons to be happily honest, happily frugal, happily generous, happily good citizens, happily fair.

I would like to see the voting strength of the MPs in parliament match the voting strengths in the country (e.g. by weighted voting in the Commons. 

Labour may be held back by its past, for it cannot easily chuck the 'Labour' tag with its confrontational approach to labour relations. What about "Ordoliberalism" ? 

Where are Labour's philosophers? The Fabians? The brains? Where, indeed, is New Labour?

Yours sincerely, Ian West (Comments to cawstein@gmail.com)

Aluminium Metabolism (2)

Some Cellular Effects of Al3+ 

Introduction

As outlined in Aluminium1, it was found that patients on dialysis for kidney failure tended to develop Dialysis Encephalopathy Syndrome (DES), and Dialysis Osteomalacia (DOM). It was further established, unequivocally, that the culprit was an excessive concentration of Al3+ in the dialysis buffer, and hence in the blood. The former syndrome (DES), which in several respects resembles Alzheimer's disease, seemed to result from accumulation of aluminium in the brain; the latter (DOM) to result from competition between Al3+ and Ca2+ at some stage in the bone-forming process. 

If excess serum Al3+ can cause either problem, it seems likely that it could, in some individual cases cause both. Searching the medical literature soon found a report of  the "Impact of Osteoporosis on the Risk of Dementia in Almost 60,000 Patients Followed in General Practices in Germany" [19]  The odd title seems to ascribe the dementia to an effect of the osteoporosis; but the impact is presumably only on the risk of dementia; i.e. it is a merely a correlation. 

How, then, does aluminium act in metabolism, and in particular in dementia? Is Al3+ a cause, or a coincidence?    

Al3+ ion Leads to Oxidative Damage.

It seems generally accepted that the presence of excess Al3+ can cause oxidative damage to cells, probably by generating the superoxide radical (O2∙-), which itself gives rise to  other reactive species such as peroxide, hydroxyl radical, and peroxynitrite. Several mechanism have been suggested: [a] mitochondria can release oxygen radicals, by incomplete reduction of oxygen to water; [b] Al3+ could displace redox-active Fe ions from their complexes; [c] mitochondria are perhaps damaged by sequestration of phosphate as Al3PO4; and [d] by direct formation of superoxide from water molecules co-ordinately bound to the Al3+ atom. Let us consider these in turn. 

[a] Mitochondria in ischaemic tissue that cannot get sufficient oxygen can develop an excessively reduced respiratory chain, with components at a sufficiently reducing potential to pass a single electron to an O2 molecule. In those circumstances the highly reactive superoxide anion is produced which can go on to react with nitric oxide, phospholipids and other components of the cell [1]. (The transfer of 1 electron to the O2 molecule generates superoxide radical (O2∙-) while the transfer of one electron to the peroxide molecule generates water and the hydroxyl radical (OH∙).)

[b] The Al3+ and the Fe3+ ions have the same high charge and similar ionic radius (57 and 64 pm respectively). Both Al3+ and Fe3+ ions bind tightly to transferrin in the blood, but the binding of Fe3+ ions is very much tighter (logKeq = 22.5 & 21.4, for Fe3+ binding to C and N sites respectively, while the binding of Al is 10 orders of magnitude less tight [2].  In the presence of Fe3+ ions, transferring does not carry Al3+, but it is not normally saturated with iron. The complexes are carried round the body in the blood plasma, and into iron-requiring cells by endocytosis. The acidic lumen of the endocytotic vesicle releases the trivalent ions.  Al3+ can then compete with Fe3+ for the many compounds in the cell that bind Al3+ more tightly than Fe3+ (such as citrate, oxalate, phosphate, acetate)[3]. There are several metabolites (such as ascorbate) that can reduce Fe3+ to Fe2+. The latter, by the Fenton reaction, can generate the destructive hydroxyl radical and tip the cell into the intrinsic (or mitochondrial) pathway of apoptosis. [4].

[c]  ATP (and ADP) mostly exits in the cytoplasm complexed with Mg2+ [5].  It is said that Al3+ inhibits hexokinase [6], as the Al3+ salt  of ATP is not a substrate. If that were true for transport into the mitochondria of ADP and Pi, the mitochondria in a cell containing Al3+ might enter the hyper-reduced state called state 4., and emit superoxide radicals [7].

[d]  The idea, ventured by  Exley and Lopez and tested in several theoretical studies [8, 9, 10], that Al3+ can generate bound superoxide directly from bound water, may be correct, but may be irrelevant. It is clear that differential binding of Al3+ to the reduced component of a redox couple would make the bound couple appear more easily reduced than the free couple. But in that case, the bound superoxide would not be as strongly reducing as free superoxide. 

Al3+ ion Displaces Mg2+ from ATP, Pi, etc..

As mentioned in [c] above, Al3+ can displace Mg2+ from ATP (and possibly ADP and Pi), under the heading of damage by oxygen radicals. Inhibition of hexokinase, and other reactions involving ATP, could have many wide-reaching effects on the metabolism of the cell including loss of ionic gradients across the cell membrane, and collapse of membrane potential.

Al3+ ion Displaces Ca2+ in the formation of bone.

It is clear, since the discovery of dialysis osteomalacia (DOM), that excess Al3+ in blood causes softening of bones. 

It is also clear that Al3+ ion gets into bone, as  half of the total body content of Al in healthy humans is found in the skeleton (and 25% in the lungs) [6].  It therefore seems clear that Al3+ can compete with and replace Ca2+ at some stage (or stages) in the bone-making process, summarised in the equation below:

10Ca2+ + 6H2PO4- + 2H2O ↔︎ Ca10(H2PO4)6(OH)2 + 14H+

Al3+ ion (probably) binds tightly to nucleophilic oxygen atoms in Nucleic acids and phosphorylated proteins.

The leather-tanning process exploits the tendency of Al3+ to form crosslinks between collagen molecules: RCOO- ...Al3+.....OH-.... Al3+.....O-OCR. And the very tight binding of Al3+ to nucleophilic oxygen atoms in ligands such as orthophosphate, acetate, citrate, and hydroxyl ions make it highly credible that Al3+ would bind to such groups in proteins and nucleic acids. Ganrot's comprehensive (but early) review of "Metabolism and possible health effects of aluminum" [6] suggested that proteins (in general) bind Al3+.  He believed that the tight binding of Al3+ to proteins and nucleic acids would be irreversible and that the ageing human would gradually fill up with aluminium. That has proved very hard to demonstrate.  Brain tissue from donors with neurodegenerative disease contain significantly more Al than control brains; but these control brains show no correlation between Al content and age [11].  

Famously, the amyloid beta protein (Aβ) of extracellular presenile plaques in Alzheimer's Disease, was said to bind Al3+, though how, where, how tightly and how many are all question that still need clarifying. 

Amyloid, so called as it takes up iodine stain 'like starch', has nothing to do with starch. It represents a misfolded form of any of some 20 different proteins, is characteristic of ageing, is insoluble, and may cause organ failure in a rather passive way [4].  The amyloid of dementia is the result of misfolded peptides (Aβ40, Aβ42 ) derived from the Amyloid Precursor Protein, APP.  More about APP and Aβ in a subsequent post.

The other characteristic feature of neurodegenerative dementia is the presence of hyper-phosphorylated Tau-protein in 'neurofibrillary tangles' (NTFs). It is suggested that the phosphorylation of tau causes it to dissociate from intracellular microtubules and migrate to form these intracellular tangles [12].  Both the fibrillar amyloid plaques of aggregated Aβ42 peptide, and the neurofibrillary tangles of  hyper-phosphorylated Tau-protein are primarily β-pleated-sheet structures [13]. 

However, it is not known if Al3+ binding has a causative rôle in plaque formation; for example, by favouring β-sheet structure over 𝛼-helix, though there have been a number of attempts to establish such an effect [14]. Miller et al. detected in amyloid plaques the  amide-1 absorbance of β-sheet and deposits of Cu and Zn, but no Al [15].  Indeed, two recent, deep and thorough reviews on the structure of  "Amyloid beta" [16, 17] make no mention of  Al3+, which seems a strange omission after 40 years of the aluminium hypothesis of dementia. 

A recent paper by the Exley group reported Al3+ deposits in the same cell as neurofibrillary tangles, but in a different location [18].

References.

[1]  Indo et al. (2015) J Clin Biochem Nutr.; 56: 1–7.)

[2]  Ott, D.B. et al. (2019) Metallomics 11(5):968-981;  doi: 10.1039/c8mt00308d.

[3]   Vekeman et al. (2021) Nanomaterials (Basel); 11: 1763; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308151/

[4]  Wikipedia

[5]  Kiss, T.; Sovago, I.; Martin, R. B. Al3+ Binding by Adenosine 5′-Phosphates: AMP, ADP, and ATP. Inorg. Chem. 1991, 30, 2130− 2132.

[6]  Ganrot, P.O., (1986) "Metabolism and possible health effects of aluminium", Environmental Health Perspectives 65, 363-441

[7]  J Bioenerg Biomembr. (1999);31(4):347-66.  doi: 10.1023/a:1005427919188.

[8] Exley, C., (1992) Free Radic. Biol. Med. 13: 79–81

[9] Mujika et al. (2014) https://doi.org/10.5936/csbj.201403002

[10] Lopez (2022) Free Radical Biology and Medicine, Volume 179, 1 February 2022, Pages 200-207.

[11] Exley C, Clarkson E. (2020) Sci Rep. 10(1):7770. doi: 10.1038/s41598-020-64734-6. 

[12] Siddhartha Mondragón-Rodríguez et al. (2020) Hindi Neural Plasticity, Volume 2020 | Article ID 2960343 | 

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