One hypothesis why neurons die in Alzheimer’s disease is the accumulation of extra-cellular amyloid-β proteins. In Alzheimer’s disease, the such proteins accumulate to form plaques and consequently cannot be dissolved and metabolised anymore.
Here’s a great video (1+h) “Alzheimer’s Disease: From Genes to Novel Therapeutics”
NIH “Wednesday Afternoon Lecture” by Rudolph Tanzi (2011)
He’s the leader of the Cure Alzheimer’s Fund Alzheimer’s Genome Project and has carried out multiple genome wide association studies of thousands of Alzheimer’s families leading to the identification of novel AD candidate genes, including CD33 and the first two rare mutations causing late-onset AD in the ADAM10 gene (see below).
From amyloid pathology to tao pathology
Tanzi states that high levels of amyloid don’t mean anything, but high levels of tau tangles do.
Tau protein abnormalities may initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.When this occurs, the microtubules disintegrate, collapsing the neuron’s transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
“In addition to beta-amyloid proteins, tau also plays a role in Alzheimer’s, creating what are called “neurofibrillary tangles” or “tau tangles”. Jack said the changes in the brain created by tau seem to occur first, but amyloid aggregation, or clumping, accelerates the changes in tau and causes it to spread.
The central message is that tau and beta-amyloid plaque interact with each other in a synergistic way, said Jack, a professor of radiology and a neuroradiologist at the Mayo Clinic College of Medicine, in Rochester, Minn.”
“The research found that the interaction between the two proteins might be the key: as these interactions increased, the progression of Alzheimer’s disease worsened.
Reddy’s paper suggests that when the interaction between the phosphorylated tau and the amyloid-β happens at brain synapses, it can damage those synapses. ”
“Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease” (Marcello et al 2013):
“The underlying neuropathology of AD includes extracellular deposition of amyloid-β and intraneuronal accumulation of aberrant forms of hyperphosphorylated tau as well as synapse dysfunction and neurodegeneration”
“A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit β-amyloid peptide (Aβ) formation in Alzheimer’s disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. ”
“ADAM10 interacts with the clathrin adaptor AP2, and this association is increased in AD patients’ hippocampus.”
- are a type of glial cell that are the resident macrophages of the brain and spinal cord, and act as active immune defense in the central nervous system (CNS).
- constitute 10-15% of the total glial cell population within the brain.
- are distributed in large non-overlapping regions throughout the brain and spinal cord.
- are constantly scavenging the CNS for plaques, damaged neurons and infectious agents.
“There are many activated microglia over-expressing IL-1 in the brains of Alzheimer patients that are distributed with both amyloid-β plaques and neurofibrillary tangles. This over expression of IL-1 leads to excessive tau phosphorylation that is related to tangle development in Alzheimer’s disease.
Many activated microglia are found to be associated with amyloid deposits in the brains of Alzheimer’s patients. Microglia interact with amyloid-β plaques through cell surface receptors that are linked to tyrosine kinase based signaling cascades that induce inflammation. When microglia interact with the deposited fibrillar forms of amyloid-β it leads to the conversion of the microglia into an activated cell and results in the synthesis and secretion of cytokines and other proteins that are neurotoxic.
One preliminary model as to how this would occur involves a positive feedback loop. When activated, microglia will secrete proteases, cytokines, and reactive oxygen species. The cytokines may induce neighboring cells to synthesize amyloid precursor protein. The proteases then possibly could cause the cleaving required to turn precursor molecules into the beta amyloid that characterizes the disease. Then, the oxygen species encourage the aggregation of beta amyloid in order to form plaques. The growing size of these plaques then in turn triggers the action of even more microglia, which then secrete more cytokines, proteases, and oxygen species, thus amplifying the neurodegeneration.”
Updated version of the Amyloid hypothesis:
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). 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.