Explain the molecular biology of amyloid-beta, plaques, tau protein and neuronal cell loss in Alzheimer's

disease, and the potential role of amyloid-beta immunotherapy

I.
Amyloid Beta
a) Amyloid beta is a product of the enzymatic degradation of Amyloid precursor protein
i.
APP is a transmembrane protein with unknown function. Theories include regulation of
synapse formation, neural plasticity, or Iron transport
ii.
APP has three enzymatic cleavage sites for the enzymes , , and Secretase
b) APP is always cleaved by Gamma, but only the combination of gamma and beta cleavage
produces amyloid deposition
i.
Gamma/Alpha secretases cleave APP in the majority of cases, this is non-pathogenic.
Alpha secretase is thought to be involved in memory formation
ii.
Gamma/Beta secretase cleavage produces the amyloid beta protein, which may exist
as a monomer, but may spontaneously change conformation and aggregate with other
A proteins, forming (generally) Extracellular amyloid plaques
1. It is thought that the Beta pathway is necessary for peripheral nerve myelination
c) Not all people produce amyloid plaques, and the process by which the Beta pathway
turns pathogenic is not greatly understood
i.
Several genetic causes have been found, though these arent the majority of cases
ii.
Mutations in APP, -secretase, or Apolipoprotein E are factors in hereditary Alzheimers
iii.
Extra copies of the APP increase risk (Down Syndrome)
d) Exactly how plaques cause neuronal degeneration is unknown. Plaques may damage
calcium homeostasis, induce apoptosis, or selectively accumulate in mitochondria causing
energy dysregulation
II.
Tau Protein
a) Tau protein is required to stabilize microtubules, which are important in neurotransmitter
vesicle movement in neurons
i.
Mainly found in the axons of CNS neurons
ii.
A plaques and the damage they cause lead to a hyperphosphorylation of tau proteins,
which causes aggregation in the dendrites, where they form neurofibrillary tangles,
further contributing to neural damage
iii.
This process also leads to the destruction of microtubules in the neurons
III.
Immunotherapy, and new drug targets
a) The first clinical trials for an Alzheimers vaccine were performed 15 years ago.
i.
Strong evidence for halting of disease progression, and even plaque clearing in mice.
ii.
Stopped at phase II. 6% chance of hydrocephalus in patients in trial
iii.
Current vaccine ideas include a DNA vaccine. Injecting the A gene in hopes that the
protein will be produced in small amounts and an immune response is mounted
b) Attempts to use immunoglobulin therapy are also being trialled
c) New drug targets include the enyzmes involved in the production of A
i.
Two drugs are currently in clinical trial, to be completed in 2019, which target BetaSecretase 1, called BACE inhibitors