Alzheimer's Research Related Products:

Amyloid Beta
Alzheimer's Disease (AD) is characterized by the presence of extracellular plaques and intracellular neurofibrillary tangles (NFTs) in the brain. The major component of these plaques is Ab peptide (b-amyloid), a 40 to 43aa peptide cleaved from amyloid precursor protein (APP). Increased release of the 'longer forms' of Ab peptide, Ab42 or Ab43, which have a greater tendency to aggregate than Ab40, occurs in individuals expressing certain genetic mutations, expressing certain ApoE alleles, or may involve other, still undiscovered, factors. Many researchers theorize that this increased release of Ab42/Ab43 leads to the abnormal deposition of Ab and the associated neurotoxicity in the brains of affected individuals.

Tau
Tau is a heterogeneous group of proteins that range in molecular weight from 50-67kD. They are instrumental in the assembly of microtubules and have been associated with some disease states. In normal brain, tau is localized in the axons of the neurons but in some neuropathological lesions, it accumulates within the body of the neuron. Tau protein is a microtubule-associated protein predominantly localized to neuronal axons. Tau promotes tubulin polymerization and the stabilization of microtubules. Hyperphosphorylated forms of Tau are the major components of paired helical filaments (PHF) found in the neurofibrillary tangles that characterize Alzheimer’s disease. Alternate splicing of tau mRNA, glycosylation, and differential phosphorylation contribute to the heterogeneity of tau.

Amyloid Precursor Protein (APP)
Amyloid Precursor Protein (APP) is an integral membrane protein with a large ectodomain, a transmembrane domain, and a short cytoplasmic tail. APP is proteolytically cleaved by b-secretase (BACE) to generate the APP N-terminal fragment (sbAPP) with Mr100kD and a C-terminal fragment (C99) with Mr12kD. The smaller 12kD fragment can be further cleaved by g-secretase, an enzyme activity recently attributed to presenilin-2. This second cleavage produces the insoluble b-amyloid (Ab), a peptide of ~4kD. The accumulation of b-amyloid in intracellular neurofibrillary tangles and extracellular plaques is observed in the brains of Alzheimer’s disease patients and Downs’s Syndrome patients.

Presenilin 1
Presenilin is a probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Presenilin requires the other members of the gamma-secretase complex to have a protease activity. It may play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. The gamma-secretase complex stimulates cell-cell adhesion through its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, it cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. Further research may implicate the complex in hematopoiesis. Defects in PSEN1 have been implicated in early-onset Alzheimer disease.

Presenilin 2
The Presenilin-2 gene was recently discovered on chromosome 1 and is responsible for an early onset form of autosomal dominant Alzheimer’s disease. The amino acid sequence is approximately 67% identical with that of the presenilin-1 protein. It also is a membrane protein that has regions where mutations have been identified in family members with Alzheimer’s disease. The sequence corresponds to the extracellular portion of this protein. The gene sequence of presenilin 2 does not match any known human gene sequences, except for that of presenilin 1, and the identity and function of both these proteins remain speculative.

Clusterin (CLU)
Clusterin, also known as Apolipoprotein J (ApoJ), is a ubiquitous multifunctional glycoprotein that can interact with a broad spectrum of molecules such as complement components, various receptors, and the Alzheimer’s b-amyloid peptide. Clusterin expression is increased in
Alzheimer’s disease brain tissue and clusterin-immunoreactive amyloid plaques are found associated with phospho-tau-positive dystrophic neurites and it has been suggested that clusterin facilitates the conversion of diffuse b-amyloid deposits into amyloid and enhances tau phosphorylation in neurites around these plaques. Other reports show that clusterin expression is decreased in proliferating cells and is upregulated in quiescent and senescent cells, suggesting that it may also play a role in aging and tumorigenesis suppression. Clusterin exists in at least two distinct isoforms.

Alzheimer's Disease

Alzheimer's disease is the most common cause of dementia and is characterized by a progressive degeneration of the central nervous system. Alzheimer’s is associated with the presence of senile plaques, neurofibrillary tangles, and massive loss of neurons. It is estimated that more than 35 million are affected by Alzheimer's disease worldwide.

The cause and progression of Alzheimer's disease (AD) are not well understood. Currently used treatments offer a small symptomatic benefit but there are no treatments currently available to delay or halt the progression of the disease. A number of life-style habits have been suggested for the prevention of Alzheimer's disease, but there is a lack of adequate evidence for a link between these recommendations and reduced degeneration. Mental stimulation, exercise, and a balanced diet are suggested, as both a possible prevention and a sensible way of managing the disease.

Both Amyloid Beta and Tau proteins have been implicated as a cause of Alzheimer's disease (1,2). Support for the amyloid beta postulate comes from the fact that people with trisomy 21 (Down Syndrome), who have an extra gene copy, almost universally exhibit AD by 40 years of age (3). In support of the amyloid beta theory is the fact that certain genetic mutations that result in the formation of plaques can cause early-onset Alzheimer’s disease, a rare form of the disease that strikes people between the ages of 30 and 60. Mutations in any of three proteins, the amyloid precursor protein (APP) or either of two presenilin proteins called presenilin 1 (PS1) and presenilin 2 (PS2), are responsible for most cases of early-onset Alzheimer’s. These mutations all result in early formation of amyloid plaques. Together, these three mutations cause an estimated 10% of all Alzheimer’s disease cases.

Normal, healthy neurons send messages to each other along axons. The structural integrity of each axon depends on a central core of long, straight proteins called microtubules that support the axon and also serve as roadways for transporting cellular cargo. Microtubules are held in place by a protein called tau. When tau is abnormal or altered it disrupts the normal axon structure and makes cellular communication difficult. The tangles that are characteristic of Alzheimer’s disease, which are also called neurofibrillary tangles (NFT), are made up of axons filled with the twisted remnants of hyperphosphorylated tau proteins. Some researchers believe that it is the tau protein and not beta-amyloid that causes neurons to become damaged and die in Alzheimer’s disease.

While everyone who dies of Alzheimer’s disease has plaques and tangles, there are certain types of plaques that can be found in the brains of people who don’t have Alzheimer’s disease. Unfortunately, it is not yet known whether people who have the plaques but no disease symptoms can live a full life and never develop the disease, or whether the plaques are an early sign of Alzheimer’s and even though they do not show symptoms of Alzheimer’s at the time the plaques are discovered, these people will eventually go on to develop the disease.

Familial Alzheimer’s Disease Genetic Factors

Most cases of AD are late-onset and sporadic, but in some cases the disease is inherited as an autosomal dominant trait. This can account for approximately 10% of the Alzheimer’s cases. Three different genes, the amyloid precursor protein (APP), and presenilins 1 and 2 (PS1 and PS2) have been implicated in the cause of familial Alzheimer’s disease.

An important part of the disease process in Alzheimer's disease is the accumulation of Amyloid beta protein; a peptide of 39–43 amino acids that appear to be the main constituent of amyloid plaques in the brains of Alzheimer’s disease patients. To form Amyloid beta, APP must be cut by two enzymes, beta secretase and gamma secretase. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP by gamma secretase. Gamma secretase can cut APP at several points within a small region of the protein that results in Amyloid beta of various lengths. The lengths associated with Alzheimer's disease are 40 and 42 amino acids long. Amyloid beta 42 is more likely to aggregate to form plaques in the brain than Amyloid beta 40. Presenilin mutations lead to an increase in the ratio of Amyloid beta 42 produced compared to Amyloid beta 40, although the total quantity of Aβ produced remains constant. This can come about by various effects of the mutations upon gamma secretase. Presenilins are also implicated in the processing of notch, an important developmental protein. Mice that have the PS1 gene knocked out die early in development from developmental abnormalities similar to those found when notch is disrupted.

Late-onset Alzheimer’s Disease Genetic Factors

In 1993, Apolipoprotein E4 was identified as being a genetic indicator of late-onset Alzheimer’s disease. Apolipoprotein E is a protein found in the brain, cerebrospinal fluid, and bloodstream. Apolipoprotein E protects brain cells and is involved in cholesterol transport (4). Three genetic forms of apolipoprotein are known. These forms are called E2, E3, and E4. About 15% of the Caucasian population has an E4 gene. Persons who inherit an E4 gene from a mother or father have a more than 3-fold risk of developing Alzheimer’s disease late in life, after age 65. People who inherit an E4 gene from both mother and father, have ten times the normal risk of developing Alzheimer’s disease after age 65. It is not clear why or how E4 increases risk. The E4 allele is not dominant. This means that not everyone with an E4 allele develops Alzheimer’s disease. In fact, only about half of those positive for an E4 allele ever develop Alzheimer’s disease. Some other factor other than the E4 is needed to produce Alzheimer’s disease. For example, factors in the environment may delay expression of the E4 gene. Genetic counselors do not advise being tested for the E4 allele, since is not certain that everyone with the E4 allele develops Alzheimer’s disease.

Recently, in 2009 two research groups, working independently in Wales and France, have identified a new set of genes that may contribute to Alzheimer's disease (5,6). The three new genes, known as clusterin (CLU), complement receptor 1 (CR1) and PICALM are linked to the most common form of the memory disorder, late-onset Alzheimer's; the type that affects patients in their 60s or later and accounts for about 90% of all Alzheimer's cases. Most healthy people have some version of the three new genes. But their presence alone does not necessarily translate to an elevated risk of Alzheimer's. Each of the genes comes in different forms, or variants, that confer different levels of risk. Some variants actually protect against Alzheimer's while others increase the risk.

Clusterin and CR1 are known to interact with the amyloid protein that builds up in the brain of Alzheimer's patients. Clusterin may be involved in helping to clear away the amyloid that forms in the brain; but another variant of the gene may also allow amyloid to form fibrils. CR1 codes for an immune system protein and may be involved in the body's ability to recognize the accumulating plaques of amyloid as foreign. PICALM is expressed in all tissues, and quite strongly in neurons, where it is involved in endocytosis at synapses. PICALM may also affect processing of amyloid precursor protein.
The identification of these new gene targets provides new avenues of investigation into Alzheimer’s disease and to the development of new potential treatments for this disease.

References:1. Hardy J, Allsop D (October 1991). "Amyloid deposition as the central event in the aetiology of Alzheimer's disease". Trends Pharmacol. Sci. 12 (10): 383–388.
2. Mudher A, Lovestone S (January 2002). "Alzheimer's disease-do tauists and baptists finally shake hands?". Trends Neurosci. 25 (1): 22–26.
3. Lott IT, Head E (March 2005). "Alzheimer disease and Down syndrome: factors in pathogenesis". Neurobiol Aging 26 (3): 383–389.
4. Polvikoski T, Sulkava R, Haltia M, et al. (November 1995). "Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein". N Engl J Med 333 (19): 1242–1247.
5. Harold et al., Nature Genetics 41, 1088 - 1093 (2009)
6. Lambert, J.-C. et al., Nature Genetics 41, 1094 - 1099 (2009)