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-alz Research and Development Alzheimer's Disease Inflammation and Immunity

Alzheimer's Disease: Working Towards a Cure

Alzheimer's disease (AD) is a common disorder affecting mainly elderly people. The duration of the disease ranges from 5 to 15 years, and exerts a tremendous toll on both patients and families. Alzheimer's disease progression results in a profoundly disturbing loss of mental capability. Lasting memories of family and a vibrant life are destroyed, leaving behind a mentally disabled person who does not remember the history of their life or the identity of family members.

There is currently no cure for AD.

Population studies indicate that 5% of the population over 65 is afflicted with AD. The probability of developing Alzheimer's increases with age such that 20% of the population develops the disease after age 80, and 50% of the population over 85 years of age become afflicted.1 Although AD is mainly an affliction of the elderly, an early onset form of the disease also occurs in younger people with significant frequency (0.1 % of the population).2

AD is the fourth most common cause of death in the industrialized world after heart disease, cancer, and stroke.

Currently, 4 million Americans and 14 million people in the industrialized world suffer from AD and this number is expected to continue to grow as the general population ages. United Nations population projection estimates that by 2050 there will be 370 million people older than 80 years of age and, in the absence of any preventative medicine, 100 million people with AD.

In the absence of an AD therapeutic, by 2050 there will be as many as 100 million people worldwide suffering from AD.3

Currently, the 4 million Americans already diagnosed with AD cost American society roughly $100 billion per year in lost wages and cost of care.4 Extrapolating these numbers for the 100 million people expected to be afflicted in 2050, produces an astounding number of $2.5 trillion per year in worldwide economic losses due to AD. The loss to humanity in non-economic terms is even greater.

AD Neuropathology

The neuropathology of AD is characterized by the accumulation of extracellular and intracellular proteinaceous deposits. Extracellular deposits include the neuritic plaques and cerebrovascular amyloid, the principle component of which is the 40-42 amino acid, self-aggregating ß-amyloid peptide (Aß40/42). Other features of AD neuropathology include hyperphosphorylated forms of tau protein, synapse and neuron loss as well as microglial activation, astrocytosis and inflammatory responses.5,6

Overproduction of Aß is believed to play a central role in the development of AD. Aß is a proteolytic peptide fragment of ß-amyloid precursor protein (APP), a transmembrane protein expressed throughout most tissues of the body.7 The APP protein is processed by at least three different proteases (α-, ß-, and y-secretases), where α-, ß- secretase cleavages generate soluble Aß peptide. Figure 1 below shows the structure of APP, the resulting proteolytic fragments, and the processing enzymes.

Schematic diagram
Figure 1. Schematic diagram of the ß-amyloid precursor protein (APP), sites of enzymatic processing and the resulting Aß peptide. The top diagram depicts the largest of the known APP forms, comprised of 770 amino acids. A single transmembrane domain (TM) at amino acids 700-723 is indicated by vertical dotted lines. The Aß fragment includes 28 amino acids outside the membrane plus the first 12-14 residues of the TM domain. Small arrows indicate sites of the proteolytic cleavage by major processing enzymes.7

Genetic Research has provided clues to the underlying causes of AD.

Genetic research has identified several pathogenetic mutations causing early onset AD, providing valuable knowledge about the underlying mechanisms of the disease. Familial early onset AD can be caused by mutations in at least three different genes, namely the ß-amyloid precursor protein (APP) gene on chromosome 21, the presenilin (PS1) gene on chromosome 14, and the PS2 gene on chromosome 1.8 These mutations generate either increased levels or more stable forms of the ß-amyloid protein (Aß).

Mutations associated with early-onset forms of AD, note Figure 2 below, have been shown to increase the production of Aß For example, a double mutation (K670N, M671L) called the Swedish mutation, located N-terminal to the ß-secretase cleavage site, results in overproduction of Aß 8 Other mutations C-terminal to the y-secretase cleavage site, T714I, V715M, I716V, and V717 I/G/F/L10,11 affect the length of the Aß peptide and enhance the production of Aß42, a more amyloidogenic form of the peptide.12 The Arctic mutation (E693G in the APP-gene) has been discovered in a family in northern Sweden in which the afflicted family members display a classical AD phenotype. The mutation is located within the AAß-peptide coding sequence which is unique, since previous APP-mutations linked to AD have been found to frame the AAß-peptide coding sequence.

Schematic diagram
Figure 2. APP and the Aß-peptide (shaded protein sequence) with presently known pathogenic mutations. The APP protein is processed by at least two different proteolytic activities to generate the secreted, soluble Aß peptide. α-secretase, responsible for the N-terminal cleavage, was recently identified and cloned.13,14,15 This enzyme, also called BACE1, preferentially releases Aß starting at Asp-1 and Glu-11. The ADAM family of proteases appears to be responsible for the α-secretase activity16 that cleaves within the Aß sequence. The y-secretase cleavage, releasing the C-termini of AAß, occurs in the predicted transmembrane domain of APP. The y-secretase consists of a complex of proteins, the most important being presenilin 1.17,18

Several mutations are associated with particular pathological phenotypes. The Dutch E693Q19 and Italian (E693K) mutations are located within the Aß-peptide coding sequence and are associated with cerebral amyloid angiopathy (CAA) and hemorrhagic stroke, while the Flemish (A692G) mutation generates parenchymal "kuru-like" amyloid plaque deposition and neurofibrillary degeneration in addition to the cerebrovascular pathology. The Arctic mutation differs phenotypically from other mutations that occur within the Aß-peptide sequence since the afflicted family members display clinical symptoms of AD with characteristic insidious onset, and early deficits in short-term memory in the absence of hemorrhagic stroke or vascular lesions on brain imaging.

The regulation of Aß production may provide a much-needed path to effective therapy.

With the identification of over 150 human mutations that cause increased levels of Aß it is now commonly accepted that increased levels of Aß causes AD. Currently, much therapeutic drug development is focused on reducing the production of Aß before it can accumulate to hazardous levels. One popular approach attempts to harness the power of proteases that degrade Aß. A group of candidate proteases such as neprilysin and insulin-degrading enzyme have been implicated as amyloid-degrading enzymes. Other candidates include cathepsin D and E, gelatinase A and B, trypsin- or chymotrypsin-like endopepdidases, aminopeptidase, and serine protease complexed with α2-macroglobulin.20 The drawback of this approach is that alteration of the activity of these degrading enzymes would also affect degradation of other important biological molecules and may only be effective in degradation of soluble Aß.

Another approach is to target processing enzymes as a means of intervention. Altering the secretase activities that create the Aß peptide would lower the circulating levels of the peptide, reduce aggregation, and thus prevent the onset of neuro-pathological processes. However, secretase enzymes also play roles in processing of other important biological molecules. Altering the activity of these processing enzymes therefore has a high risk of side effects.

Using novel proprietary screening techniques, Icogenex is developing an effective small molecule therapeutic that will normalize the production of Aß without disrupting other healthy biological processes within the body. Our goal is to develop an effective therapy for the treatment or prevention of AD.

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