The majority of AD cases occurs sporadically and begins in elderly individuals over 65-70 years of age. A small percentage of AD cases are familial and transmitted in an autosomal dominant fashion. Familial AD generally develops at a much earlier age of onset compared to sporadic AD.
At the neuropathological level, the AD brain is characterized by two hallmark lesions, amyloid plaques and neurofibrillary tangles.
Extracellular amyloid plaques were first described by Alois Alzheimer in 1906.
These plaques consist of largely insoluble deposits of a protein peptide called beta-amyloid (Aβ), together with other proteins, remnants of neurons, and non-nerve cells such as microglia.
Aβ is derived from a larger protein called amyloid precursor protein (APP).
APP is associated with the cell membrane, but its normal function in the cell is not yet fully known.
In AD, plaques develop first in areas of the brain used for memory and other cognitive functions.
Most people develop some plaques in their brain tissue as they age. However, the AD brain has a significantly higher number of these deposits in certain brain regions. Aβ clusters at an earlier stage in the plaque development process and forms so called Aβ -derived diffusible ligands, or ADDLs (also known as soluble oligomers). Recent experimental evidence suggest a primary pathogenic role of these non-fibrillary Aβ oligomers in initiating synaptic dysfunction that ultimately leads to neuronal degeneration and dementia in AD.
Liberation of the harmful Aβ protein from its precursor requires two proteolytic events to cleave the peptide at its amino and carboxyl termini. These are referred to as the beta- and gamma- secretase sites, respectively. Gamma-secretase mediated cleavage of APP yields also an intracellular fragment called the APP intracellular domain (AICD) that is involved in transcriptional activities.
The second hallmark of AD pathology, also found and described by Alois Alzheimer, consists of abnormal collections of twisted protein threads found inside nerve cells. The main component of these structures, called neurofibrillary tangles, is a protein called tau.
In AD, an abnormally high number of additional phosphate molecules attach to tau. As a result of this phosphorylation process, tau disengages from the microtubules and begins to aggregate with other threads of tau. Ultimately, these tau threads form tangles, the microtubules disintegrate and the neuron’s transport system collapses. This may result first in malfunctions in communication between neurons and later in the death of the cells.
Genetic studies in AD have focused on two key issues: 1) whether a gene might influence a person’s overall risk of developing the disease and 2) whether a gene might influence the age at which the disease begins. To date, only four of the approximately 30,000 genes in the human genome have been conclusively shown to affect AD development.
Mutations in three genes - the APP gene found on chromosome 21, the PS1 gene (Presenilin) on chromosome 14, or the PS2 gene on chromosome 1 – are linked to the rare early-onset form of familial AD. The APP gene encodes the precursor protein to Aβ. The presenilin genes code for proteins that are components of the gamma-secretase complex which plays an essential part in cleaving APP to form Aβ. Presenilin gene mutations promote the breakdown of APP, leading to increased production of harmful Aβ.
A fourth gene on chromosome 19 encodes a protein called apolipoprotein E (ApoE). ApoE carries lipids in the bloodstream and is important in clearing lipids from the blood. APOE, the gene that encodes ApoE, has three common alleles: ε2, ε3, and ε4. The ε4 allele is a risk factor gene for the common late-onset AD. The ε2 allele may provide some protection against AD and ε3 is thought to play a neutral role.
Although investigations of the genetic basis have greatly enhanced our understanding of the biology of Alzheimer’s disease (AD), dominant genetic defects account only for a small percentage of cases. The etiology of the much more frequent sporadic AD is still largely unknown. However, both early- and late-onset forms of AD are characterized by the same neuropathological hallmarks, pointing to the importance of additional modulatory factors involved in the pathophysiology of the disease.
One of these potential modulators is Reelin, a large extracellular glycoprotein with a fundamental role in neuronal positioning during brain development. This highly conserved protein also binds to ApoE receptors and is a pivotal synaptic regulator which indirectly exerts broad control over synaptic function and plasticity in the adult brain.
How could Reelin affect the formation of the two neuropathological hallmarks of AD; amyloid plaques and neurofibrillary tangles?
Our experiments have shown that Reelin-mediated signaling favors amyloidogenic APP processing and enhance fibrillary Aβ peptide production. Moreover, impaired Reelin signaling results in elevated Tau phosphorylation and facilitates the formation of neurofibrillary tangles around amyloid-β plaques.