Alzheimer’s disease (AD) is characterized by cognitive deterioration affecting 5 million people in the USA.


PATHOGENESIS
The brain of Azheimer’s patients marked by extracellular amyloid-beta deposits and intracellular neurofibrillary tangles. Amyloid-beta peptide (A-beta) may be at the root of neurodegeneration and the mechanism by which amyloid-beta induces neurotoxicity appears to be mediated by oxidative stress.

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APP CLEAVAGE
The A-beta of different sizes, A-beta(1-40) and (1-42) results from the cleavage of the amyloid precursor protein (APP) which is a ubiquitously expressed integral membrane protein that is cleaved in two distinct pathways following transportation to the pre-synaptic terminal (Figure 1.).

In the non-amyloidogenic pathway, the cleavage of APP by alpha-secretase release a soluble APP-alpha which is thought to regulate neuronal excitability, plasticity, and survival; and leaves an 83 amino acid carboxy terminal APP fragment.

In the amyloidogenic pathway, the cleavage of APP by beta-secretase, which is a membrane-bound aspartyl protease (BACE), generates a 99 amino acid C-terminal APP fragment, which can be internalized and further cleaved by the gamma-secretase complex. The gamma-secretase is a large protein complex residing in cell surface and also in the endoplasmic reticulum and Golgi membrane consists of several proteins including presenilin 1 and 2 and regulates the cleavage of a number of single transmembrane proteins. The resulting A-beta peptides aggregate and form plaques which is a characteristic feature of Alzheimer’s brain. The cleavage of the 99 amino acid fragment also liberates an intracellular APP domain that can translocate to the nucleus and regulate gene expression including apoptotic genes.



Figure 1. Non-amyloidogenic and amyloidogenic processing of APP. APP, amyloid precursor protein; α-sec, alpha-secretase; BACE, beta-secretase; C83, 83 amino acid carboxy terminal APP fragment; C99, 99 amino acid C-terminal APP fragment; sAPPa, soluble APP-alpha peptide; sAPPß, soluble APP-beta peptide; Ab40/42, A-beta (1-40) and (1-42); γ-sec, gamma-secretase; iAPP, APP intracellular fragment.

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GENETIC MUTATIONS
In the familial cases, the mutation in either the APP gene or the presenilin 1 gene result in increased production of A-beta peptides. For example, mutation in APP identified in a Swedish family alters two amino acids preceding the A-beta amino terminus and causes enhanced beta-secretase cleavage. Moreover, mutations in presenilin 1 gene results in an increase in the A-beta (1-42)/(1-40) ratio, which is an important aspect of familiar Alzheimer’s disease.
Although, genes have been implicated in AD, these cases only encircle 1% of all AD patient and the rest fall into category called sporadic meaning that the mechanism of these cases are still elusive.

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Amyloid-beta peptide
Both A-beta peptides are toxic; however, the insoluble A-beta is more capable of aggregating into plaques. The mechanism by which A-beta peptides induces neurotoxicity appears to be mediated by oxidative stress (Figure 2.).
A-beta aggregates are able to interact with cell membranes and form non-specific ion channels, which results in increase of intracellular calcium influx triggering the production of reactive species. Also, it can produce hydrogen peroxide directly by scavenging transition metals such as copper or iron, initiating the production of other ROS such as the highly reactive hydroxyl radical which can attack DNA, proteins and fatty acids.




Figure 2. Potential target reactive species producing pathways by A-beta peptide. AA, arachidonic acid; Aß, Amyloid-beta peptide; CuSOD, copper-dependent superoxide dismutase; MnSOD, manganese superoxide dismutase; NMDA, N-metil-D-aspartate receptor; nNOS, neuronal nitric-oxide synthase; ONOO-, peroxynitrite; •O2-, superoxide; PLA2, phospholipase A2.

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