Protein of the Month

July 2006






Molecule of the Month: APP




ExPASy Protein Spotlight


Amyloid-b Precursor Protein

By Jennifer McDowall


            Alzheimer’s disease (AD) is the most common form of dementia in the elderly.  A progressive neurodegenerative disease, AD is characterised by memory loss, confusion, impaired judgement, personality changes, loss of language skills, and eventually by death.  In AD patients, brain cells that process, store and retrieve information degenerate and die, resulting in a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and neocortex.  Amyloid  (or senile) plaques and neurofibrillary tangles are hallmarks of the disease.  Although the direct cause of AD is still unclear, a prime suspect is amyloid-b peptide (Ab), which accumulates in brain tissue in AD patients, forming extracellular deposits of amyloid plaques composed primarily of aggregated amyloid-b peptide.  Plaques similar to those found in AD patients have also been found in some variants of Lewy Body Dementia, and coating cerebral blood vessels in Cerebral Amyloid Angiopathy.  Amyloid-b is a protein fragment derived from the breakdown of amyloid-b precursor protein (APP). 


Amyloid-b Precursor Protein, Still an Enigma.


            APP is a conserved glycoprotein embedded in the membrane surrounding neuronal cells, protruding both inside and outside the cell.  APP consists of a large N-terminal extracellular domain, a short hydrophobic transmembrane domain, and a short intracellular C-terminal domain.  Mutations in APP, or in proteins that process APP, have been linked with familial Alzheimer’s disease (FAD), causing early-onset of symptoms, possibly by affecting APP processing that in turn alters Ab production and plaque formation.  Individuals with Down’s Syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer’s symptoms, possibly through the over-production of APP, and therefore of Ab.

            However, APP has a role to play besides Ab production, appearing to have a number of important developmental and postnatal neurological functions.   These functions may be elicited through the N-terminal extracellular domain or the C-terminal cytoplasmic domain, both regions appearing to have important roles in neurogenesis and neuronal regeneration. 

The N-terminal extracellular domain is cysteine-rich and similar in structure to growth factors such as hepatocyte growth factor.  It also has both heparin and copper-binding sites.  This domain may function as a cell surface receptor on the surface of neurons, contributing to neurite growth, neuronal adhesion and axonogenesis, as well as cell mobility.  APP acts as a kinesin I membrane receptor to mediate the axonal transport of b-secretase and presenilin 1.  The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix.  APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death.

The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions.  APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters. 


Next:  Amyloid Plaque Formation