Causes of Alzheimer's Disease

Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles. The major component of amyloid plaques is beta amyloid and the chief component of neurofibrillary tangles is the Tau protein. In 1990s, researchers have focused on beta amyloid, but recently they found that Tau could play a central role.

Beta Amyloid

Beta amyloid (Aβ) is a peptide generated from its precursor protein (APP) by the enzyme called secretase. Its length varies between 40 and 42 amino acids. Longer Aβ peptides are more likely to aggregate, thereby more toxic than shorter Aβ. The secretase has three different forms: α, β, and γ. Mutations of the γ-secretase are associated with a rare genetic disorder called early-onset familial AD. The affected person may develop AD as early as age 30. It has been shown that the mutation increases the production of more toxic Aβ (see The Beta Amyloid). On the other hand, cholesterol-lowering drugs such as statins can reduce the risk of AD. The mechanism is also related to the production of Aβ (see Prevention).

Another more common genetic risk factor is apolipoprotein E (apoE), which has three major isoforms: apoE2, apoE3 and apoE4. People with ApoE4 are more likely to develop AD. The underlying mechanism is not clear, but it could also be related to Aβ (reference).

The neurotoxicity of Aβ is linked to calcium (Ca²⁺) dysregulation. It has been demonstrated that Aβ can induce influx of extracellular Ca²⁺ into the neuronal cytoplasm (review). Ca²⁺ is known to influence various cellular processes. In a normal cell, cytosolic Ca²⁺ is tightly regulated. Dysregulation of Ca²⁺ will lead to neuronal damages and death.

Thus, early studies supported the notion that beta amyloid is central to the development of AD. In later studies, however, a number of findings have led researchers to shift attention from beta amyloid to the Tau protein.

The Tau Protein

Tau is produced from its gene located in chromosome 17. Mutations in the Tau gene cause several genetic disorders including frontotemporal dementia. This demonstrates that dysfunction of the Tau protein alone is sufficient to result in neurodegeneration (reference). In an experimental study where the Tau gene was knocked out from the mouse DNA, it was found that tau-depleted neurons showed no signs of degeneration in the presence of Aβ. This provides direct evidence that Tau is essential to Aβ-induced neurotoxicity (reference). Experiments have further shown that aggregated Aβ peptides can activate an enzyme called glycogen synthase kinase-3β (GSK3β), which is important for Aβ-induced neurotoxicity (reference). The function of this enzyme is to catalyze protein phosphorylation.

Protein phosphorylation is a process that adds a phosphate group to a protein, particularly on the amino acid serine, threonine or tyrosine. It is widely used to regulate cellular processes, but aberrant phosphorylation may result in abnormal functions. In the neurofibrillary tangles observed in AD brain, the Tau protein is hyperphosphorylated, namely, too many amino acid residues are phosphorylated.

A clear picture is now emerging: hyperphosphorylation of Tau is the origin of AD and the neurotoxicity of Aβ is mediated by the enzyme GSK3β which stimulates hyperphosphorylation. However, there remains an important question: how does Tau hyperphosphorylation cause neurodegeneration? In the fetal brain, Tau is highly phosphorylated but it is normal (reference). Knowing the detailed mechanism may help to develop effective drugs against AD.

For many years, researchers thought the neurotoxicity of Tau proteins were due to their aggregation into neurofibrillary tangles. This view is supported by the finding that hyperphosphorylated Tau proteins are more likely to aggregate than normal Tau. Recent evidence, however, indicates that hyperphosphorylated Tau can cause neurodegeneration, without the need to form neurofibrillary tangles (reference).

Tau is a microtubule-associated protein (MAP) which regulates the assembly and stability of microtubule networks. This function led some researchers to suggest that Tau hyperphosphorylation may affect microtubule networks, but there was no convincing evidence to support this view. Although hyperphosphorylated Tau may lose its function to stabilize microtubule networks, it may not disrupt already established microtubule networks. Indeed, it was observed that hyperphosphorylated Tau impaired its ability to bind microtubules, but did not lead to disturbance of microtubule networks (reference). In another study, Aβ was shown to disrupt axonal transport without affecting microtubule stability (reference).

Microtubules are a major component of cytoskeleton which exists in all kinds of animal and plant cells. There are several types of MAPs to regulate their assembly and stability. The Tau protein is unique in that it is present only in neurons and predominantly localized in axons. This unique feature suggests that Tau may have an additional function that is specific to neurons. Further details are discussed in another page.

Author: Frank Lee
Last updated: February 20, 2011