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leading to aggregation include mainly oxidative modifications (23-26). Besides
oxidative modifications, phosphorylation of the tau protein was shown to
accelerate aggregation (27) and decrease the normal turnover of tau (28).
Moreover, the disturbance of the balance between protein synthesis and pro-
teolytic degradation might be another reason for the accumulation of cross-
linked proteins such as ceroid or lipofuscin (29). As mentioned, the accumulation
of the aggregated proteins is more dramatic in postmitotic cells such as neurons,
since formed aggregates are not divided (and thus diluted) into daughter cells
upon cell division. During lifetime, neurons may accumulate tremendous
amounts of aggregated proteins filling up to 75% of the cellular volume (30),
and this high level of accumulation may cause an increase in the susceptibility
to apoptosis (31).
Interestingly, a study by Di Domenico et al. identified selective protein
targets which are oxidized in aged rats. Most of the oxidatively modified pro-
teins were found to be the key proteins involved in energy metabolism and
ATP production. Oxidative modification of these proteins was associated with
decreased enzyme activities (32).
4.1.2 Alzheimer's Disease
AD is the most common age-related disorder worldwide and accounts for a
total of about 60% of all existing neurodegenerative diseases. This disease was
first described by the German physician and researcher Alois Alzheimer. Clini-
cal symptoms include the loss of memory and sense of direction and orienta-
tion. Following the disruption of motor neurons, impairment in the motor
coordination may occur. Physiological outcomes include the intracellular for-
mation of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated
tau protein and extracellular accumulation of
-amyloid aggregates (33). The
resulting physical outcomes include brain atrophy, loss of neurons and syn-
apses, mostly found in the temporal, frontal, and parietal cortex, as well as in
hippocampus and amygdala. The survival time with the disease is approxi-
mately 9 years after diagnosis and death is mainly caused by pneumonia.
Alternative/pathological enzymatic cleavage of the amyloid precursor
protein (APP) results in
β
β
-amyloid peptide formation. The enzymes involved
in this process are the
β
- (also termed BACE1) and
γ
-secretases. First, cleavage
performed by
β
-secretase results in sAPP
β
and smaller fragment C99, and
later by
β 42 , the major types of amyloid peptides
accumulating in the AD brain (Fig. 4.2). Presenilin-1 and presenilin-2 (PS1 and
PS2) are transmembrane proteins playing roles in the A
γ
-secretase results in A
β 40 or A
-peptides related
senile plaque formation. They have been identified as parts of
β
-secretase
enzyme complex and are involved in the maturation of APP. While the over-
expression of these proteins resulted in increase of APP
γ
α
and A
β 40 , the inhibi-
tion of PS1 and PS2 caused a decrease in
-secretase activity. APPs are thought
to be involved in calcium homeostasis (34), cell growth, adhesion (35), axional
vesicle transport (36), and regulations of free metal ions (37). Knockout mice
γ
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