Alzheimer's Disease Research

Pathogenesis of Alzheimer's Disease

Historically, AD has been suggested to be caused by a loss of cholinergic neurons and a decrease in acetylcholine production. However, lack of efficacy of pharmacological treatments targeting the cholinergic system has led to declining popularity of this hypothesis.

The current model of AD pathogenesis involves the formation of two histopathological features in the CNS; neurofibrillary tangles (NFTs) and senile plaques.

NFTs are intracellular structures localized within neurons that are formed from paired helical filaments (PHFs). The core protein within PHFs is tau, a microtubule-associated protein that is hyperphosphorylated in the brains of AD sufferers. Tau hyperphosphorylation is an early event in AD pathogenesis and is mediated by cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase 3β (GSK-3β). Hyperphosphorylated tau can not be incorporated into microtubules and aggregates in neuronal cells, forming PHFs and subsequently NFTs.

Senile plaques are formed by deposits of amyloid fibrils in the extracellular environment of the brain. Amyloid fibrils are formed from the oligomerization of amyloid β (Aβ) peptides into insoluble polymers. Aβ peptides are formed from the proteolytic cleavage of amyloid precursor protein (APP) by α-, β- and γ-secretases into Aβ(1-40) and Aβ(1-42) proteins. Aβ(1-42) is much more fibrillogenic than Aβ(1-40), thus is the pathological form of the protein. Aβ(1-42) plaques accumulate in brain regions such as the cerebellum, striatum and thalamus, where they are implicated in the development of AD. Furthermore, abberant trafficking of APP by kinesin-I has a role in the development of this disease.

In AD, neuronal loss is caused by several mechanisms. Aβ peptides induce high levels of oxygen- and nitrogen-reactive species and reduce endogenous levels of antioxidants, which play a central role in the destruction of neurons. Oxidative damage to lipids and membrane proteins causes synaptic loss and white matter rarefraction, which are characteristics of AD. Aβ peptides increase the vulnerability of neurons to excitotoxicity through upregulation of ionotropic glutamate receptors, furthering oxidative damage and neural loss. Tau has been proposed to be an essential mediator in this process.

Reactive astrocytes and activated microglia surround senile plaques in AD and produce chemotatic factors and complement proteins. Aβ binds Cq1 and activates the complement-dependent membrane attack complex (MAC), causing local toxicity to neurons. In addition, neurotoxicity is mediated through induction of inflammatory mediators such as IL-1β and TNF-α. Neuronal apoptosis also occurs in AD and is induced by Aβ-activated caspase-2.

This progressive Aβ-mediated neuritic and synaptic injury alters neuronal homeostasis and is a contributing factor in the abnormal functioning of cdk5 and GSK-3β, which cause tau hyperphosphorylation. Thus, it is fair to conclude that Aβ plays an initiating role in the pathogenic AD cascade that results in altered tau metabolism.

Pharmacological Interventions

There is no cure for AD. Current pharmacological interventions for AD are limited and mainly act to alleviate symptoms. They include acetylcholinesterase inhibitors, ionotropic glutamate receptor antagonists and antipsychotics. There is intense research into developing treatments for AD with some focusing on immunotherapy and vaccination against APP or Aβ, as well as development of ligands to the more conventional pharmacological targets.