In 1991, the
amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease.
[37][38] Support for this postulate comes from the location of the gene for the
amyloid beta precursor protein (APP) on
chromosome 21, together with the fact that people with
trisomy 21 (
Down Syndrome) who have an extra
gene copy almost universally exhibit AD by 40 years of age.
[39][40] Also
APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain.
[41] Further evidence comes from the finding that
transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.
[42]
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.
[43] Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication.
[44] One receptor for Aβ oligomers may be the
prion protein, the same protein that has been linked to
mad cow disease and the related human condition,
Creutzfeldt-Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.
[45]
In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by ageing-related processes in later life to cause the neuronal withering of Alzheimer's disease.
[46] N-APP, a fragment of APP from the peptide's
N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as
TNFRSF21).
[46] DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the
ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.
A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss.
[47] This observation supports the
tau hypothesis, the idea that
tau protein abnormalities initiate the disease cascade.
[38] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form
neurofibrillary tangles inside nerve cell bodies.
[48] When this occurs, the
microtubules disintegrate, collapsing the neuron's transport system.
[49] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
[50]
New drug for treating prion-related brain diseases
Originally Posted by Markas
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