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A biochemical marker is 'a substance whose detection indicates a biochemical (chemical, molecular, and physical) activity or change in the body, its tissues or cells; the biochemical marker may be monitored in the assessment of a disorder or condition' (Genzyme Corporation, 2011). In particular, biochemical markers are needed to reflect the pathogenesis of Alzheimer's disease, that is, they are required for determination of the extent of the disease, for treatment and for the prediction of resistance to anticipated treatments. Alzheimer's disease is an age-dependent dementia which is associated with loss of neurons mainly in the basal forebrain and hippocampus, and brain shrinkage (Rang et al., 2007). The cerebrospinal fluid is continuously in direct contact with the space of the central nervous system and thus biochemical changes of the brain are reflected in this region (Hampel et al., 2009). Biochemical hallmarks taken from this region include the aggregates formed by amyloid peptide protein known as β-amyloid(Aβ), and the proteins found in the neurofibrillary tangles called phosphorylated tau (p-tau) and total tau (t-tau) (Parnetti et al., 2005). How the body gives rise to each of these biochemical markers and how these particular constituents are indicative of Alzheimer's disease in an individual are questions which remain ambiguous. However research in this field is ongoing to explore these ideas of biochemical markers in greater detail.
An important biochemical marker of Alzheimer's disease is the main protein component of senile plaques known as β-amyloid(Aβ). A single membrane-spanning protein known as the amyloid precursor protein(APP) produces this soluble protein, Aβ. The APP gene is found on chromosome 21 and is metabolized according to two unique pathways. The first pathway begins when a protease known as α-secretase cleaves APP within the Aβ domain, which results in the release of an N-terminal derivative referred to as 'α-secretase-cleaved soluble APP'(αsAPP). This molecule is further cleaved by γ-secretase, releasing a peptide known as P3(Andreasen et al., 200). In Alzheimer's disease however, the APP molecule is cleaved by β-secretase at the N-terminus resulting in the release of 'β-secretase-cleaved soluble APP'(β-sAPP) (Blennow et al., 2003). This fragment is then further cleaved by γ-secretase which results in free Aβ depositing in the extracellular amyloid plaques (Siemers et al., 2010). Aβ's mechanism of action is to cause neurotoxicity, which includes induction of apoptosis, structural damage, damage to the synapse, oxidative stress, inflammation and the formation of amyloid pores (Hampel et al., 2009). There are two important variants of Aβ with either 40 or 42 amino acids, consecutively known as Aβ(1-40) and Aβ(1-42). The primary constituent of these plaques are Aβ(1-42) since this variant has the highest tendency to aggregate and is faster at forming plaques (Parnetti et al., 2005). When this Aβ variant precipitates in extracellular amyloid plaques there is a decrease in its concentration and thus this change can be used as a biochemical marker of Alzheimer's disease (Blennow et al., 2003). This variant however is not an ideal marker since a decrease in the concentration of Aβ(1-42) can also reflect other dementias and neurological disorders. Moderately low concentrations can be indicative of Lewy-body dementia, a condition which is also distinguished by senile plaques (Bibl et al., 2010). Furthermore, even though a decrease in the concentration of Aβ displays a trait characteristic of Alzheimer's disease, this factor is not limited to this particular condition alone.
Other biochemical markers of Alzheimer's disease are the proteins found in the neurofibrillary protein aggregates known as total tau (t-tau) and phosphorylated tau (p-tau) (Mandelkow et al., 1998). In general, axonal microtubules work to establish cell polarity, cell processes and intracellular transport. In normal cells, tau is the microtubule-associated protein which stabilizes these microtubules. Tau is a very hydrophilic molecule and is encoded by a single gene. It can be phosphorylated at many sites, some of which control its binding properties and which are useful as diagnostic tools for Alzheimer's disease (Mandelkow et al., 1998). In Alzheimer's disease, tau displays abnormal phosphorylation and an imbalance of kinases/ phosphatases at several sites. These activities are currently thought to be a consequence of Aβ's neurotoxicity (Hampel et al., 2009). As a result of this phosphorylation, there is a loss of binding that causes the tau to detach from the tubules. Consequently, the microtubules breakdown and neuron degeneration occurs. Tau then aggregates into two strands known as 'paired helical filaments'(PHFs) and in this form the microtubule structure is lost and the filaments assemble into neurofibrillary tangles inside the neuron (Mandelkow et al., 1998). Two particular markers are given rise during these physiological changes and these are known as t-tau, which signifies the total concentration of the tau protein and p-tau, which corresponds to the concentration of phosphorylated tau. In Alzheimer's disease there is a change in the intensity of each tau entity and this change is thought to reflect death of the neurons with the release of tau related proteins in the cerebrospinal fluid (Hampel et al., 2009). Total tau simply indicates neuronal and axonal degeneration and/or damage and thus a moderate increase in t-tau is due to this outcome (Blennow et al., 2003). The degree of increase is once again not restricted to Alzheimer's disease since high concentrations of t-tau are also seen in disorders with intense neuronal degeneration such as in Creutzfeldt-Jakob disease (Hampel et al., 2010). On the other hand, the concentration of phosphorylated tau in the cerebrospinal fluid, reflects the presence of p-tau in the brain and hence the formation of tangles in Alzheimer's disease (Parnetti et al., 2005). High concentrations of p-tau have only been related to patients with Alzheimer's disease and normal concentrations reflect patients with psychiatric disorders, with chronic neurological disorders and so forth. Moreover, the specificity of p-tau in the discrimination between Alzheimer's disease and other dementias is higher than t-tau and Aβ(1-42) (Blennow et al., 2003).
Concisely, an ideal biochemical marker for Alzheimer's disease should detect an essential feature of the neuropathology and should ultimately have diagnostic sensitivity for Alzheimer's disease (Hampel et al., 2010). Although amyloid Aβ peptides in plaques, total tau and phosphorylated tau are currently the main features characteristic of the condition, Aβ and t-tau are still not entirely appropriate biochemical markers to completely differentiate Alzheimer's disease from other disease states (Blennow et al., 2003). Unfortunately, since the range of versatile biochemical markers is limited, clinical research is still underway to discover the ideal biochemical markers of Alzheimer's disease (Blankenstein et al., 2011).