Biomedical Engineering Reference
In-Depth Information
demonstrated to be a major factor in causing the disease.
6-8
Ab peptides are
produced from the amyloid precursor protein (APP) by proteolytic cleavage at
the b-secretase and g-secretase sites. b-Secretase cleaves APP to produce the
carboxyl terminal b-secretase fragment (CTFb), which is then cleaved by g-
secretase to produce Ab (Figure 6.1). Ab of different lengths is generated by
different cleavages by the g-secretase, the most common being 40 (Ab(1-40)) or
42 (Ab1-(42)) residues. Another protease, functionally called a-secretase,
competes with b-secretase and cleaves APP within the Ab sequence to produce
soluble APP alpha (sAPPa), which has neuroprotective effects,
9
and which
precludes Ab production (Figure 6.1).
The majority of AD patients express wild-type APP (WT APP) of sporadic
AD that is not linked to genetic mutations,
1,2
but a few families express
APP containing mutations which result in Ab accumulation and development
of the disease.
3-5
Because the mutant APP forms produce more Ab, expression
of mutant APP forms has been useful in developing animal models to identify
A Production in Regulated and Constitutive Secretory Pathways of Neurons
Action
Potential
ß-Amyloid
Regulated
Secretion
Aß
Aß
Aß
Protein precursor Active Peptides
Secretases:
Aß Accumulation:
Multimers
Aggregates
Amyloid plaques
APP
A
Regulated
Secretory vesicles
Proteases
Constitutive
Secretory vesicles
Cell Death
and
Memory Loss
A peptides
Neurotoxic
Figure 6.1
Ab production in the regulated secretory pathway of neurons provides
extracellular Ab that causes memory loss. Ab peptides are generated by
proteolytic processing of the amyloid precursor protein (APP) in secretory
vesicles that undergo axonal transport from the neuronal cell body to nerve
terminals, where Ab is secreted. Secretory vesicles of the regulated secretory
pathway (yellow circles) provide the majority of secreted, extracellular Ab
peptides.
15,40,41
Some Ab is also provided by the basal, constitutive secretory
pathway (constitutive secretory vesicles shown as blue circles). Intracellular
production of Ab within secretory vesicles occurs by cleavage at the N-
terminus of Ab within APP, achieved by proteases known as b-secretases,
and cleavage at the C-termini of Ab within APP which is achieved by
g-secretases. Proteolytic processing by b-andg-secretases results in Ab
peptides of 40 and 42 residues, known as Ab(1-40) and Ab(1-42). Extra-
cellular Ab peptides in brain accumulate as oligomers and aggregates in
amyloid plaques, and cause loss of memory in Alzheimer's disease.
