Neuronal death in Alzheimer's disease and therapeutic opportunities

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD; however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. In the past decade, enormous efforts have been devoted to understand the genetics and molecular pathogenesis leading to neuronal death in AD, which has been transferred into extensive experimental approaches aimed at reversing disease progression. Modern medicine is facing an increasing number of treatments available for vascular and neurodegenerative brain diseases, but no causal or neuroprotective treatment has yet been established. Almost all neurological conditions are characterized by progressive neuronal dysfunction, which, regardless of the pathogenetic mechanism, finally leads to neuronal death. The particular emphasis of this review is on risk factors and mechanisms resulting in neuronal loss in AD and current and prospective opportunities for therapeutic interventions. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.

Figure 1

Processing of APP. APP can be processed by different sets of enzymes: one pathway leads to amyloid plaque formation (amyloidogenic), while the other does not (non-amyloidogenic). In the non-amyloidogenic pathway, APP is cleaved first by α-secretase to yield a soluble N-terminal fragment and a C-terminal fragment integrated within the cellular membrane. The soluble protein may be involved in the enhancement of synaptogenesis, neurite outgrowth and neuronal survival, and is considered to be neuroprotective. The membrane fragment of the cleaved APP is acted upon by γ-secretase, a tetrameric complex comprised presenilins, nicastrin, Aph1 and Pen2, to yield a soluble N-terminal fragment (P3) and a membrane-bound C-terminal fragment. In the amyloidogenic pathway, APP is cleaved first by β-secretase, yielding a soluble N-terminal fragment and a membrane-bound C-terminal fragment. The membrane fragment is then cleaved by γ-secretase, yielding a membrane-bound C-terminal fragment and a soluble N-terminal fragment (Aβ). While Aβ is required for neuronal function, it can aggregate in the extracellular space of the brain to form amyloid plaques.

Figure 2

Activation of complement system by the amyloid plaques and its dual role in neuronal death. C1q binds to the boxed sequence in aggregated amyloid peptides and activates classical pathway of complement system. This leads to cleavage of C3 to C3b which could bind to a different sequence from the amyloid peptide (boxed). C3b initiates generation of C5-convertase cleaving C5 into C5a and C5b. C5a interacts with the C5a receptor (C5aR) on the surface of neurons and activates the neuroprotective mitogen activated protein kinases. On the other hand, C5b initiates the terminal pathway of complement cascade which forms MAC which integrates into membrane of the weakly protected neurons resulting in their death.