• The Cholinergic theory emerged in the late 1970s when British
neuroscientist Peter Davies and colleagues reported that AD sufferers
had decreased levels of the enzyme which helps synthesise Acetylcholine.
• Earlier studies had shown that drugs which block the cholinergic
system interrupt memory functioning.
• These two findings underpinned the argument that the core deficit
in AD was a lack of the neurotransmitter acetylcholine.
•This theory provided pharmaceutical companies with a plausible
rationale for the development of drug treatment.
(Travis 2005)
• In 1984 the characteristic plaques found in the brains of AD
sufferers were shown to comprise mostly of a 4kDa protein fragment called
ß-amyloid (Aß).
• Aß peptide is formed by proteolytic cleaving of amyloid
precursor protein (APP).
• There are 2 forms of Aß peptide – Aß40 (contains
40 amino acids, accounts for ~90% of Aß) and Aß42 (containing
42 amino acids accounts for ~10% Aß released from cells). Aß42
is the predominant form of amyloid found in plaques.
• The amyloid theory suggests that dysregulation of APP processing
causes overproduction of Aß42 which can coalesce into a deposit
of loosely arranged peptides called ‘diffuse plaques’.
• The diffuse plaques facilitate the further deposition of Aß.
During the maturation of the plaque, Aß peptides form ß-pleated
sheets and fibrilise.
• The formation of mature neuritic plaques causes microglial and
astrocytic activation, oxidative stress, tau aggregation and phosphorylation.
Ultimately neuronal loss and synaptic dysfunction occur and results in
dementia.
(Verdile et. al. 2004)
• In 1991 research into several families which
showed the rare early-onset familial AD were found to have a mutation
in the gene encoding APP.
• Similar disease causing mutations have also been found on genes
encoding proteins presenilin 1 (PS1) and presenilin 2 (PS2) and these
were shown to affect APP processing.
• The APP, PS1 and PS2 genes influence Aß deposition, either
by increasing Aß production, increasing the production of the more
pathological Aß42 species or enhancing Aß aggregation.
• In further support of this hypothesis, it has been shown that
neuronal degradation occurs in close proximity to amyloid plaques, and
Aß has been shown to induce neural degeneration both in vitro and
in vivo.
(Travis 2005)
• Neurofibrillary tangles (NFTs) are insoluble
filamentous accumulations which are found in degenerating neurones of
AD sufferers.
• The main constituent of NFTs is a cytoskeletal protein called
tau. Under normal conditions, tau binds with microtubules and regulates
their state of polymerisation and stability.
• In AD, tau becomes hyperphosphorylated (overloaded with phosphate
groups) and self aggregates. This prevents microtubule binding and axonal
transport, causes degeneration of dendrites and axons, and ultimately
results in neuronal death.
• NFTs are often found in the hippocampus, enthorinal cortex and
amygdala.
• Although the majority of researchers concentrate on the amyloid
hypothesis, some have argued that NFTs are central to AD pathogenesis.
Interest in the tau theory has increased in recent years following work
carried out in 1998, which showed that mutations in a gene encoding for
one of the tau proteins caused a rare form of dementia in which NFTs also
occur.
(Nicholls 2004)
