A Medley of Potpourri

Monday, October 24, 2022

Politics of South Africa

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Politics_of_South_Africa

The Republic of South Africa is a unitary parliamentary democratic republic. The President of South Africa serves both as head of state and as head of government. The President is elected by the National Assembly (the lower house of the South African Parliament) and must retain the confidence of the Assembly in order to remain in office. South Africans also elect provincial legislatures which govern each of the country's nine provinces.

Since the end of apartheid in 1994 the African National Congress (ANC) has dominated South Africa's politics. The ANC is the ruling party in the national legislature, as well as in eight of the nine provinces (Western Cape is governed by the Democratic Alliance). The ANC received 57.50% of the vote during the 2019 general election. It had received 62.9% of the popular vote in the 2011 municipal election. The main challenger to the ANC's rule is the Democratic Alliance, led by John Steenhuisen (previously by Mmusi Maimane), which received 20.77% of the vote in the 2019 election. Other major political parties represented in Parliament include the Economic Freedom Fighters and the Inkatha Freedom Party, which mainly represents Zulu voters. The formerly dominant New National Party, which both introduced and ended apartheid through its predecessor the National Party, disbanded in 2005 to merge with the ANC. Jacob Zuma served as President of South Africa since 9 May 2009 until his resignation in February 2018. Zuma was replaced by Cyril Ramaphosa. The country's 2019 general election was held on 8 May.

The Economist Intelligence Unit rated South Africa a "flawed democracy" in 2019. Some argue that South Africa represents a dysfunctional state.

Context

The Prime Ministers of the British Dominions attending the 1926 Imperial Conference with King George V seated in the center.

Nelson Mandela was the first democratically elected President of South Africa.

On 31 May 1910, the Cape Colony, Natal Colony, Transvaal and the Orange River Colony were united in one state called the Union of South Africa. The Union of South Africa adopted a system of governance based on the political system of the United Kingdom. The British monarch was the ceremonial head of state of South Africa and was represented by a Governor-General. Real political power lay in the hands of the Prime Minister and Cabinet. The basic ideas of this system such as a three branch government and strong Parliament remain in force today.

On 15 November 1926, the Balfour Declaration was adopted at the 1926 Imperial Conference. This document made the dominions of the British Empire including South Africa equal to each other and the United Kingdom. In practice, this made the Union of South Africa a self-governing dominion of the British Empire. The Union of South Africa became formally independent in 1931 when the Statute of Westminster was passed. It gave the Parliament of South Africa the power to make laws for South Africa without the approval of the Parliament of the United Kingdom.

In 1948, the National Party of South Africa adopted a policy of institutional racial segregation called apartheid. People of colour, especially the majority black population, were deprived of the few rights they had. Racial classification and discrimination was used to distribute economic resources and control political power. The white population, particularly the Afrikaners, controlled the political system. Black people were disenfranchised in all provinces of South Africa.

In 1961, South Africa became a Republic. The British monarch was replaced as head of state by a President elected by the minority of the population through elected representatives. In 1970, the Homeland Citizens Act was passed. It built on the system of reservations for the indigenous black African population to create a system of superficially independent black countries. Many Black people were deprived of their South African citizenship and instead became citizens of the Bantustan of their tribe. They were not recognized by a majority of the world's countries and the extent of their independent control over internal affairs was highly limited.

The African National Congress (ANC) led the fight against this system of apartheid. After intense international pressure and domestic struggle, the De Klerk government repealed or relaxed many apartheid laws. After negotiations between the ANC, Inkatha Freedom Party, NP and other organizations, apartheid was formally abolished and the Interim Constitution was passed. The Bantustans were abolished and reintegrated into South Africa and their citizens regained South African citizenship.

The Government of National Unity (GNU) established under the interim constitution ostensibly remained in effect until the 1999 national elections. The parties originally comprising the GNU – the African National Congress (ANC), the National Party (NP), and the Inkatha Freedom Party (IFP) – shared executive power. On 30 June 1996, the NP withdrew from the GNU to become part of the opposition.

Many of the principles of racial equality, majority democracy and minority rights that it established were translated into the final Constitution of South Africa that was adopted in 1996 and which remains in force. It sets out the structure of the government, protects fundamental human rights, creates mechanisms of accountability and divides legislative and executive power among the national, provincial and local spheres of government.

Government

The Houses of Parliament in the legislative capital of Cape Town is the seat of the Parliament.

The Union Buildings in the administrative capital of Pretoria.

The seat of the Supreme Court of Appeals is located in the judicial capital of Bloemfontein.

South Africa is a parliamentary representative democratic republic, wherein the President of South Africa, elected by parliament, is the head of government, and of a multi-party system. It consists of three branches.

The executive branch consists of the President of South Africa and the Cabinet of South Africa. The President is elected by the Parliament of South Africa for a five-year term. The President may only serve two terms. By convention this position is occupied by the leader of the largest party in the National Assembly. The President appoints other members of the Cabinet called Ministers. Ministers oversee executive government departments. The Cabinet forms and executes policy and most legislative proposals originate from the Cabinet. The President and members of the Cabinet are accountable to the National Assembly. It has the power to remove them from office by passing a motion of no confidence and it has the power to hold them accountable through oral and written replies to questions from Members of Parliament.

The legislative branch consists of the Parliament. The Parliament consists of two chambers: the upper house is the National Council of Provinces (NCOP) and the lower house is the National Assembly. In practice, the National Assembly is by far the more powerful house. It controls the composition of the government and its approval is required for most legislative proposals to become law. The NCOP provides equal representation to South Africa's nine provinces and its approval is required for laws that affect South Africa's provinces and cultural communities. Whereas the National Assembly is elected by party proportional representation, the NCOP is elected by the legislatures of each province.

The judicial branch consists of the courts. It interprets and enforces laws. The highest court for constitutional matters is the Constitutional Court of South Africa. It has the power to strike down laws that conflict with the Constitution. The Supreme Court of Appeals is the highest court for non-constitutional matters. The High Court of South Africa is a court of general jurisdiction with appellate powers. It is divided into divisions that have authority over a geographic region of the country. Magistrate Courts serve as courts of first instance. There are specialized courts and tribunals with power that can be equivalent to the Supreme Court of Appeals.

Constitution

The Constitutional Court is seated in Johannesburg on Constitution Hill. It is the final arbiter of the constitution and its decisions are binding on all courts in the Republic

Following the 1994 elections, South Africa was governed under an interim constitution. This constitution required the Constituent Assembly (CA) to draft and approve a permanent constitution by 9 May 1996. The present constitution was passed in 1996 and promulgated by President Nelson Mandela in 1997. It is the highest law in the land; all other laws are expected to abide by and conform to the principles of the constitution. The Constitution not only sets out the structure of the three branches of government and the fundamental human rights of all of South Africa's people, but it provides for the management of public funding, the delineation of the boundaries and organization of Provinces, the formation of Chapter 9 Institutions to hold the government accountable.

Political parties and their current vote share

General elections take place every 5 years. The first fully non-racial democratic election was held in 1994, the second in 1999, the third in 2004, the fourth in 2009, the fifth in 2014, and the most recent in 2019. Until 2008, elected officials were allowed to change political party, while retaining their seats, during set windows which occurred twice each electoral term, due to controversial floor crossing legislative amendments made in 2002. The last two-floor crossing windows occurred in 2005 and in 2007.

After the 2009 elections, the ANC lost its two-thirds majority in the national legislature which had allowed it to unilaterally alter the constitution.

The Congress of South African Trade Unions (COSATU) and the South African Communist Party (SACP) are in a formal alliance with the ruling ANC (the so-called Tripartite Alliance), and thus do not stand separately for election.


Party		Votes	%	+/–	Seats	+/–
	African National Congress	10,026,475	57.50	–4.65	230	–19
	Democratic Alliance	3,622,531	20.77	–1.36	84	–5
	Economic Freedom Fighters	1,882,480	10.80	+4.45	44	+19
	Inkatha Freedom Party	588,839	3.38	+0.98	14	+4
	Freedom Front Plus	414,864	2.38	+1.48	10	+6
	African Christian Democratic Party	146,262	0.84	+0.27	4	+1
	United Democratic Movement	78,030	0.45	–0.55	2	–2
	African Transformation Movement	76,830	0.44	New	2	New
	Good	70,408	0.40	New	2	New
	National Freedom Party	61,220	0.35	–1.22	2	–4
	African Independent Congress	48,107	0.28	–0.25	2	–1
	Congress of the People	47,461	0.27	–0.40	2	–1
	Pan Africanist Congress	32,677	0.19	–0.02	1	0
	Al Jama-ah	31,468	0.18	+0.04	1	+1
	African Security Congress	26,262	0.15	New	0	New
	Socialist Revolutionary Workers Party	24,439	0.14	New	0	New
	Black First Land First	19,796	0.11	New	0	New
	African People's Convention	19,593	0.11	–0.06	0	–1
	Afrikan Alliance of Social Democrats	18,834	0.11	New	0	New
	Capitalist Party of South Africa	15,915	0.09	New	0	New
	Alliance for Transformation for All	14,266	0.08	New	0	New
	Agang South Africa	13,856	0.08	–0.20	0	–2
	Azanian People's Organisation	12,823	0.07	–0.04	0	0
	Independent Civic Organisation	12,386	0.07	–0.01	0	0
	Minority Front	11,961	0.07	–0.05	0	0
	Democratic Liberal Congress	10,660	0.06	New	0	New
	Better Residents Association	9,179	0.05	–0.03	0	0
	Forum for Service Delivery	7,564	0.04	New	0	New
	Front National	7,144	0.04	+0.01	0	0
	Land Party	7,074	0.04	New	0	New
	African Covenant	7,019	0.04	New	0	New
	Patriotic Alliance	6,660	0.04	–0.03	0	0
	African Democratic Change	6,499	0.04	New	0	New
	Economic Emancipation Forum	6,321	0.04	New	0	New
	Women Forward	6,108	0.04	New	0	New
	Christian Political Movement	4,980	0.03	New	0	New
	African Content Movement	4,841	0.03	New	0	New
	International Revelation Congress	4,247	0.02	New	0	New
	National People's Front	4,019	0.02	New	0	New
	African Renaissance Unity Party	3,860	0.02	New	0	New
	African Congress of Democrats	3,768	0.02	New	0	New
	South African National Congress of Traditional Authorities	3,714	0.02	New	0	New
	Compatriots of South Africa	3,406	0.02	New	0	New
	People's Revolutionary Movement	2,844	0.02	New	0	New
	Power of Africans Unity	2,685	0.02	New	0	New
	Free Democrats	2,580	0.01	New	0	New
	South African Maintenance and Estate Beneficiaries Association	2,445	0.01	New	0	New
	National People's Ambassadors	1,979	0.01	New	0	New
Total		17,437,379	100.00	–	400	0

Valid votes		17,437,379	98.67
Invalid/blank votes		235,472	1.33
Total votes		17,672,851	100.00
Registered voters/turnout		26,756,649	66.05
Source: Electoral Commission of South Africa

Human rights

The constitution's bill of rights provides extensive guarantees, including equality before the law and prohibitions against discrimination; the right to life, privacy, property, and freedom and security of the person; prohibition against slavery and forced labour; and freedom of speech, religion, assembly, and association. The legal rights of criminal suspects also are enumerated. It also includes wide guarantees of access of food, water, education, health care, and social security. The constitution provides for an independent and impartial judiciary, and, in practice, these provisions are respected.

Citizens' entitlements to a safe environment, housing, education, and health care are included in the bill of rights, and are known as secondary constitutional rights. In 2003 the constitutional secondary rights were used by the HIV/AIDS activist group the Treatment Action Campaign as a means of forcing the government to change its health policy.

Violent crime, including violence against women and children, and organised criminal activity are at high levels and are a grave concern. Partly as a result, vigilante action and mob justice sometimes occur.

Some members of the police are accused of applying excessive force and abusing suspects in custody; as a result, the number of deaths in police custody remains a problem. In April 1997, the government established an Independent Complaints Directorate to investigate deaths in police custody and deaths resulting from police action.

Some discrimination against women continues, although it has improved overall, and discrimination against those living with HIV/AIDS has been becoming a serious issue.

As of 2010, there has been a growing political intolerance and repression in regards to the persons in power.

Notable politicians

Many leaders of former bantustans or homelands have had a role in South African politics since their abolition.

Mangosuthu Buthelezi was chief minister of his Kwa-Zulu homeland from 1976 until 1994. In post-apartheid South Africa he has served as President of the Inkatha Freedom Party. He was a Minister in President Mandela's cabinet. He also served as acting President of South Africa when President Nelson Mandela was overseas.

Bantubonke Holomisa, who was a general in the homeland of Transkei from 1987, has served as the president of the United Democratic Movement since 1997. Today he is a Member of Parliament.

General Constand Viljoen was a former chief of the South African Defence Force, who, as a leader of the Afrikaner Volksfront, sent 1500 of his militiamen to prop up the government of Lucas Mangope and to contest the termination of Bophuthatswana as a homeland in 1994. He co-founded the Freedom Front in 1994. He retired from being a Member of Parliament before his death in 2020.

Lucas Mangope, former chief of the Motsweda Ba hurutshe-Boo-Manyane tribe of the Tswana, ex-president of the former bantustan of Bophuthatswana, was the leader of the United Christian Democratic Party.

Kaffir (racial term)

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Kaffir_(racial_term)

Kaffir (/ˈkæfər/, Afrikaans: "kaffer") is an ethnic slur which is used in reference to black Africans in South Africa. Derived from the Arabic word Kafir meaning "nonbeliever", particularly of Islam. In the form of cafri, it evolved from its religious origins during the pre-colonial period in Eastern and Southern Africa, where the term was adopted by colonists in reference to the monotheistic, non-Islamic Bantu peoples, and it was eventually used in reference to any black person during the Apartheid era. This designation came to be considered a pejorative by the mid-20th century, and today it is considered extremely offensive.

In 2000, the South African parliament enacted the Promotion of Prevention of Unfair Discrimination Act, which has among its primary objectives the prevention of hate speech terms such as kaffir. When describing the term, the euphemism the K-word is now often used instead of kaffir.

Etymology

The term has its etymological roots in the Arabic word (Arabic: كافر kāfir) that is usually translated into English as "disbeliever" or "non-believer" to describe "one without religion" or by a Muslim to describe an atheist or someone who denies the existence of a God. The word is non-racial and applied to non-Muslims in general, and therefore in the past to non-Muslims who were encountered along the Swahili coast by Arab traders. The trade the Arabs engaged in was partly based on slavery. The Portuguese who arrived on the East African coast in 1498, encountered the usage of the term by the coastal Arabs but less so by the Muslim Swahili who used the term Washenzi (meaning "uncivilized") to describe the non-Islamic people of the African interior. The poet Camões used the plural form of the term (cafres) in the fifth canto of his 1572 poem Os Lusíadas. Variations of the word were used in English, Dutch, and, later, in Afrikaans, from the 17th century to the early 20th century as a general term for several different people groups in Southern Africa. In Portuguese, French and Spanish, the equivalent cafre was used.

From the Portuguese the term was passed onto their Asian possessions and today it exists in several Asian languages which include words such as "Khapri" in Sinhalese and "Kaapiri" in Malayalam. The terms are descriptive of the pagan natives of Cafreria, but they are not considered offensive in either Western India or Sri Lanka.

The term acquired a distinctly derogatory meaning in the context of South African history, especially during the Apartheid era. In Afrikaans, the term is more commonly spelled kaffer and became a common word used by European settlers. Through time "Kaffir" tended, in mid-20th century Southern Africa, to be used as a derogatory term for bantu black people, and in South Africa today, the term is legally regarded as hate speech.

Historical usage

Early English

The 16th century explorer Leo Africanus described the Cafri as non-Islamic "negroes", and one of five principal population groups in Africa. According to him, they were "as blacke as pitch, and of a mightie stature, and (as some thinke) descended of the Jews; but now they are idolators." Leo Africanus identified the Cafri's geographical heartland as being located in remote southern Africa, an area which he designated as Cafraria.

Following Leo Africanus, the works of Richard Hakluyt designate this population as "Cafars and Gawars, which is, infidels or misbeleeuers". Hakluyt refers to slaves ("slaues called Cafari") and certain inhabitants of Ethiopia ("and they vse to goe in small shippes, and trade with the Cafars") by two different but similar names. The word is also used in allusion to a portion of the coast of Africa ("land of Cafraria"). On early European maps of the 16th and 17th centuries, southern Africa was likewise called by cartographers Cafreria.

Colonial period

The word was used to describe monotheistic peoples (Nguni ethnic groups in particular) of South Africa, who were not of a Christian or of an Islamic religious background, without derogatory connotations, during the Dutch and British colonial periods until the early twentieth century. It appears in many historical accounts by anthropologists, missionaries and other observers, as well as in academic writings. For example, the Pitt Rivers Museum in Oxford originally labeled many African artifacts as "Kaffir" in origin. The 1911 Encyclopædia Britannica made frequent use of the term, to the extent of having an article of that title.

The late nineteenth–early twentieth century novelist, H. Rider Haggard, frequently used the term "kaffir" in his novels of dark Africa, especially those of the great white hunter, Allan Quatermain, as a then inoffensive term for black people in the region.

Similar non-derogatory usage can be found in the John Buchan novel Prester John from 1910.

Apartheid-era South Africa

During the South African general election in 1948, those who supported the establishment of an apartheid regime campaigned under the openly racist slogan "Die kaffer op sy plek" ("The kaffir in his place").

In the case of Butana Almond Nofomela, while working as an undercover policeman during the early 1980s, Nofomela stabbed to death a Brits farmer, Lourens. Nofomela had only intended to rob the wealthy tiller, but Lourens confronted him with a firearm and called him kaffir. This enraged Nofomela, who then killed the farmer.

The Afrikaans term Kaffir-boetie (Kaffir brother) was also often used to describe a white person who fraternised with or sympathized with the cause of the black community.

Namibia

Much as in South Africa the term was used as a general derogatory reference to blacks. A 2003 report by the Namibian Labour Resource and Research Institute states:

Kaffir in the Namibian context was a derogatory term which mainly referred to blacks in general but more particularly to black workers as people who do not have any rights and who should also not expect any benefits except favours which bosses ('baas') could show at their own discretion.

Modern usage

Post-apartheid South Africa

In 2000, the parliament of South Africa enacted the Promotion of Prevention of Unfair Discrimination Act. The Act's primary objectives include the prevention of hate speech terms, such as kaffir:

To promote equality
To prohibit and prevent unfair discrimination (either on the basis of age, race, sex, disability, language, religion, culture, etc.)
To prevent hate speech (e.g. calling people names such as kaffir, koelies, hotnot, etc.)
To prevent harassment

Notwithstanding the end of Apartheid and the above-mentioned Act, usage of the word in South Africa continues today.

In February 2008, there was huge media and public outcry in South Africa after Irvin Khoza, then chairperson of the 2010 FIFA World Cup organizing committee, used the term during a press briefing in reference to a journalist.

A statement made during the 5 March 2008 sitting of the South African Parliament shows how the usage of the word is seen today:

We should take care not to use derogatory words that were used to demean black persons in this country. Words such as Kaffir, coolie, Boesman, hotnot and many others have negative connotations and remain offensive as they were used to degrade, undermine and strip South Africans of their humanity and dignity.

The phrase the K-word is now often used to avoid using the word itself, similar to the N-word, used to represent nigger.

In 2012, a woman was jailed overnight and fined after pleading guilty to crimen injuria for using the word as a racial slur at a gym.

In July 2014, the Supreme Court of Appeal upheld a 2012 conviction for offences of crimen injuria and assault relating to an argument about parking in which a man used the word. The judgement states:

The word kaffir is racially abusive and offensive and was used in its injurious sense ... in this country, its use is not only prohibited but is actionable as well. In our racist past it was used to hurt, humiliate, denigrate and dehumanise Africans. This obnoxious word caused untold sorrow and pain to the feelings and dignity of the African people of this country.

In March 2018, Vicki Momberg became the first woman to be convicted of racist language for using the term over 40 times at two South African police officers.

Examples

Some indicative examples:

Mahatma Gandhi: "The latest papers received from South Africa, unfortunately for the Natal Government, lend additional weight to my statement that the Indian is cruelly persecuted being in South Africa ... A picnic party of European children used Indian and Kaffir boys as targets and shot bullets into their faces, hurting several inoffensive children." – Letter to the editor of The Times of India, 17 October 1896.
Winston Churchill, during the Boer War, wrote of his "irritation that Kaffirs should be allowed to fire on white men".
John Philip Sousa's 1914 concert suite "Tales of a Traveler", composed after his band's tour to South Africa, contains a movement titled "The Kaffir on the Karoo".
At the start of the 1946 Sherlock Holmes film Terror by Night, the narrator speaks of a famous diamond "First touched by the fingers of the humble kaffir..." while a black man is shown picking up a stone from the ground.
Kaffir is the title of a 1995 hit song by the black Johannesburg Kwaito artist Arthur Mafokate. The lyrics say, "don't call me a kaffir". This song is considered one of the first hits of the Kwaito genre, and is said to have set precedent for the post-apartheid generation struggle of combining dance music with the new phenomenon of freedom of expression in South Africa.
Kaffir Boy is the title of Mark Mathabane's autobiography, who grew up in the township of Alexandra, travelled to the United States on a tennis scholarship, and became a successful author in his adoptive homeland.
In the film Lethal Weapon 2, South African criminal Arjen Rudd (played by Joss Ackland), his colleague Pieter Vorstedt (played by Derrick O'Connor) and their followers frequently refer to Danny Glover's character Roger Murtaugh, who is African American, as a "kaffir". His partner Detective Martin Riggs (Mel Gibson) is referred to as a "kaffir-lover". At the end of the movie when Riggs and Murtaugh kill off the villains (who were smuggling illicit drugs hidden in coffee), Murtaugh says they were "de-kaffirnated".
South African cricket players complained that they were racially abused by some spectators during a December 2005 Test match against host country Australia held in Perth. Makhaya Ntini, a black player in the team, was taunted with the word "kaffir". Other white players such as Shaun Pollock, Justin Kemp, Garnett Kruger were subjected to shouts of kaffirboetie, an Afrikaans term which means "brother of a kaffir".
Australian tennis player Brydan Klein was fined $16,000 following a qualifying match at the Eastbourne International, June 2009, for unsportsmanlike conduct after allegedly calling his South African opponent, Raven Klaasen, a "kaffir".
In the film Blood Diamond (2006), Leonardo DiCaprio's character Danny Archer refers to Djimon Hounsou's character Solomon Vandy as a kaffir, which triggers the start of a vicious fistfight.

Kaffir lime

"Kaffir lime" is one of the names of a citrus fruit native to tropical countries in South and South East Asia. Its etymology is uncertain, but most likely was originally used by Muslims as a reference to the location the plant grew, which was in countries populated by non-Muslims (Hindus and Buddhists). Under this interpretation, the plant name shares an origin with the South African term, both ultimately derived from kafir, the Arabic word for "non-believer". The fruit name as such never had any offensive connotations, but due to the present negative connotations of "Kaffir" The Oxford Companion to Food recommends that the alternative term "makrut lime" be favored when speaking of this fruit.

Amyloid beta

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Amyloid_beta

Amyloid beta peptide (beta-APP)

A partially folded structure of amyloid beta(1 40) in an aqueous environment (pdb 2lfm)

Identifiers

Symbol

APP

2lfm / SCOPe / SUPFAM

amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)

Processing of the amyloid precursor protein

Identifiers

Symbol

APP

Alt. symbols

AD1

Other data

Chr. 21 q21.2

Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers (known as "seeds") can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

A study has suggested that APP and its amyloid potential is of ancient origins, dating as far back as early deuterostomes.

Normal function

The normal function of Aβ is not well understood. Though some animal studies have shown that the absence of Aβ does not lead to any obvious loss of physiological function, several potential activities have been discovered for Aβ, including activation of kinase enzymes, protection against oxidative stress, regulation of cholesterol transport, functioning as a transcription factor, and anti-microbial activity (potentially associated with Aβ's pro-inflammatory activity).

The glymphatic system clears metabolic waste from the mammalian brain, and in particular amyloid beta. Indeed, a number of proteases have been implicated by both genetic and biochemical studies as being responsible for the recognition and degradation of amyloid beta; these include insulin degrading enzyme. and presequence protease The rate of removal is significantly increased during sleep. However, the significance of the lymphatic system in Aβ clearance in Alzheimer's disease is unknown.

Disease associations

Aβ is the main component of amyloid plaques, extracellular deposits found in the brains of people with Alzheimer's disease. Aβ can also form the deposits that line cerebral blood vessels in cerebral amyloid angiopathy. The plaques are composed of a tangle of Aβ oligomers and regularly ordered aggregates called amyloid fibrils, a protein fold shared by other peptides such as the prions associated with protein misfolding diseases.

Alzheimer's disease

Research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease.^[ It is generally believed that Aβ oligomers are the most toxic. The ion channel hypothesis postulates that oligomers of soluble, non-fibrillar Aβ form membrane ion channels allowing the unregulated calcium influx into neurons that underlies disrupted calcium ion homeostasis and apoptosis seen in Alzheimer's disease. Computational studies have demonstrated that also Aβ peptides embedded into the membrane as monomers with predominant helical configuration, can oligomerize and eventually form channels whose stability and conformation are sensitively correlated to the concomitant presence and arrangement of cholesterol. A number of genetic, cell biology, biochemical and animal studies support the concept that Aβ plays a central role in the development of Alzheimer's disease pathology.

Brain Aβ is elevated in people with sporadic Alzheimer's disease. Aβ is the main constituent of brain parenchymal and vascular amyloid; it contributes to cerebrovascular lesions and is neurotoxic. It is unresolved how Aβ accumulates in the central nervous system and subsequently initiates the disease of cells. Some researchers have found that the Aβ oligomers induce some of the symptoms of Alzheimer's disease by competing with insulin for binding sites on the insulin receptor, thus impairing glucose metabolism in the brain. Significant efforts have been focused on the mechanisms responsible for Aβ production, including the proteolytic enzymes gamma- and β-secretases which generate Aβ from its precursor protein, APP (amyloid precursor protein). Aβ circulates in plasma, cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) mainly as soluble Aβ40 Amyloid plaques contain both Aβ40 and Aβ42, while vascular amyloid is predominantly the shorter Aβ40. Several sequences of Aβ were found in both lesions. Generation of Aβ in the central nervous system may take place in the neuronal axonal membranes after APP-mediated axonal transport of β-secretase and presenilin-1.

Increases in either total Aβ levels or the relative concentration of both Aβ40 and Aβ42 (where the former is more concentrated in cerebrovascular plaques and the latter in neuritic plaques) have been implicated in the pathogenesis of both familial and sporadic Alzheimer's disease. Due to its more hydrophobic nature, the Aβ42 is the most amyloidogenic form of the peptide. However the central sequence KLVFFAE is known to form amyloid on its own, and probably forms the core of the fibril.^{[citation needed]} One study further correlated Aβ42 levels in the brain not only with onset of Alzheimer's disease, but also reduced cerebrospinal fluid pressure, suggesting that a build-up or inability to clear Aβ42 fragments may play a role into the pathology.

The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is not conclusively established. An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease. Mice that are genetically engineered to express oligomers but not plaques (APP^E693Q) develop the disease. Furthermore, mice that are in addition engineered to convert oligomers into plaques (APP^E693Q X PS1ΔE9), are no more impaired than the oligomer only mice. Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated, as has aggregation of alpha synuclein.

Cancer

While Aβ has been implicated in cancer development, prompting studies on a variety of cancers to elucidate the nature of its possible effects, results are largely inconclusive. Aβ levels have been assessed in relation to a number of cancers, including esophageal, colorectal, lung, and hepatic, in response to observed reductions in risk for developing Alzheimer's disease in survivors of these cancers. All cancers were shown to be associated positively with increased Aβ levels, particularly hepatic cancers. This direction of association however has not yet been established. Studies focusing on human breast cancer cell lines have further demonstrated that these cancerous cells display an increased level of expression of amyloid precursor protein.

Down syndrome

Adults with Down syndrome had accumulation of amyloid in association with evidence of Alzheimer's disease, including declines in cognitive functioning, memory, fine motor movements, executive functioning, and visuospatial skills.

Formation

Aβ is formed after sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein of undetermined function. APP can be cleaved by the proteolytic enzymes α-, β- and γ-secretase; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 30-51 amino acid residues in length. The most common isoforms are Aβ₄₀ and Aβ₄₂; the longer form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the shorter form is produced by cleavage in the trans-Golgi network.

Genetics

Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease (familial AD, fAD). This form of AD accounts for no more than 10% of all cases, and the vast majority of AD is not accompanied by such mutations. However, familial Alzheimer's disease is likely to result from altered proteolytic processing. This is evidenced by the fact that many mutations that lead to fAD occur near γ-secretase cleavage sites on APP.

One of the most common mutations causing fAD, London Mutation, occurs at codon 717 of the APP gene, and results in a valine to isoleucine amino acid substitution. Histochemical analysis of the APP V717I mutation has revealed extensive Aβ pathology throughout neuroaxis as well as widespread cerebral amyloid angiopathy (CAA).

The gene for the amyloid precursor protein is located on chromosome 21, and accordingly people with Down syndrome have a very high incidence of Alzheimer's disease.

Structure and toxicity

Amyloid beta is commonly thought to be intrinsically unstructured, meaning that in solution it does not acquire a unique tertiary fold but rather populates a set of structures. As such, it cannot be crystallized and most structural knowledge on amyloid beta comes from NMR and molecular dynamics. Early NMR-derived models of a 26-aminoacid polypeptide from amyloid beta (Aβ 10–35) show a collapsed coil structure devoid of significant secondary structure content. However, the most recent (2012) NMR structure of (Aβ 1-40) has significant secondary and tertiary structure. Replica exchange molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states; more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis. By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states, with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment.

Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure. In contrast, soluble oligomers prepared in the presence of detergents seem to feature substantial beta sheet content with mixed parallel and antiparallel character, different from fibrils; computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.

The suggested mechanisms by which amyloid beta may damage and cause neuronal death include the generation of reactive oxygen species during the process of its self-aggregation. When this occurs on the membrane of neurons in vitro, it causes lipid peroxidation and the generation of a toxic aldehyde called 4-hydroxynonenal which, in turn, impairs the function of ion-motive ATPases, glucose transporters and glutamate transporters. As a result, amyloid beta promotes depolarization of the synaptic membrane, excessive calcium influx and mitochondrial impairment. Aggregations of the amyloid-beta peptide disrupt membranes in vitro.

In AD brains, in addition to the characteristic aggregation of Aβ peptides that causes amyloid (senile) plaques, DNA damages also accumulate. Reactive oxygen species may be the major source of DNA damage in AD brains. CDK5 kinase phosphorylates APP at threonine 568 which stimulates Aβ peptide accumulation, and CDK5 activities also affect the DNA damage response, supporting the concept of a linkage of DNA damage with AD.

Intervention strategies

Researchers in Alzheimer's disease have identified several strategies as possible interventions against amyloid:

β-Secretase inhibitors. These work to block the first cleavage of APP inside of the cell, at the endoplasmic reticulum.
γ-Secretase inhibitors (e. g. semagacestat). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aβ and its toxic fragments.
Selective Aβ₄₂ lowering agents (e. g. tarenflurbil). These modulate γ-secretase to reduce Aβ₄₂ production in favor of other (shorter) Aβ versions.

β- and γ-secretase are responsible for the generation of Aβ from the release of the intracellular domain of APP, meaning that compounds that can partially inhibit the activity of either β- or γ-secretase are highly sought after. In order to initiate partial inhibition of β- and γ-secretase, a compound is needed that can block the large active site of aspartyl proteases while still being capable of bypassing the blood-brain barrier. To date, human testing has been avoided due to concern that it might interfere with signaling via Notch proteins and other cell surface receptors.

Immunotherapy. This stimulates the host immune system to recognize and attack Aβ, or provide antibodies that either prevent plaque deposition or enhance clearance of plaques or Aβ oligomers. Oligomerization is a chemical process that converts individual molecules into a chain consisting of a finite number of molecules. Prevention of oligomerization of Aβ has been exemplified by active or passive Aβ immunization. In this process antibodies to Aβ are used to decrease cerebral plaque levels. This is accomplished by promoting microglial clearance and/or redistributing the peptide from the brain to systemic circulation. Antibodies that target Aβ and are currently in clinical trials included aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab. Amyloid beta vaccines that are currently in clinical trials include CAD106 and UB-311. However literature reviews have raised questions as to immunotherapy's overall efficacy. One such study assessing ten anti-Ab42 antibodies showed minimal cognitive protection and results within each trial, as symptoms were too far progressed by the time of application to be useful. Further development is still required for application to those who are presymptomatic to assess their effectiveness early into disease progression.
Anti-aggregation agents such as apomorphine, or carbenoxolone. The latter has commonly been used as a treatment for peptic ulcers, but also displays neuroprotective properties, shown to improve cognitive functions such as verbal fluency and memory consolidation. By binding with high affinity to Aβ42 fragments, primarily via hydrogen bonding, carbenoxolone captures the peptides before they can aggregate together, rendering them inert, as well as destabilizes those aggregates already formed, helping to clear them. This is a common mechanism of action of anti-aggregation agents at large.
Studies comparing synthetic to recombinant Aβ₄₂ in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant Aβ₄₂ had a faster fibrillation rate and greater toxicity than synthetic amyloid beta 1-42 peptide.
Modulating cholesterol homeostasis has yielded results that show that chronic use of cholesterol-lowering drugs, such as the statins, is associated with a lower incidence of AD. In APP genetically modified mice, cholesterol-lowering drugs have been shown to reduce overall pathology. While the mechanism is poorly understood it appears that cholesterol-lowering drugs have a direct effect on APP processing.
Memantine is an Alzheimer's disease drug which has received widespread approval. It is a non-competitive N-methyl-D-aspartate (NMDA) channel blocker. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. It is an option for the management of those with moderate to severe Alzheimer's disease (modest effect). The study showed that 20 mg/day improved cognition, functional ability and behavioural symptoms.

Measuring amyloid beta

Micrograph showing amyloid beta (brown) in amyloid plaques of the cerebral cortex (upper left of image) and cerebral blood vessels (right of image) with immunostaining.

Imaging compounds, notably Pittsburgh compound B, (6-OH-BTA-1, a thioflavin), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET imaging, is used to image areas of plaque deposits in those with Alzheimer's.

Post mortem or in tissue biopsies

Amyloid beta can be measured semiquantitatively with immunostaining, which also allows one to determine location. Amyloid beta may be primarily vascular, as in cerebral amyloid angiopathy, or in amyloid plaques in white matter.

One sensitive method is ELISA which is an immunosorbent assay which utilizes a pair of antibodies that recognize amyloid beta.

Atomic force microscopy, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of amyloid beta in vitro.

Vibrational microspectroscopy is a label-free method that measures the vibration of molecules in tissue samples. Amyloid proteins like Aβ can be detected with this technique because of their high content of β-sheet structures. Recently, the formation of Aβ fibrils was resolved in different plaque-types in Alzheimer's disease, indicating that plaques transit different stages in their development.

Dual polarisation interferometry is an optical technique which can measure early stages of aggregation by measuring the molecular size and densities as the fibrils elongate. These aggregate processes can also be studied on lipid bilayer constructs.