Amyloid Beta Peptide

Clinical Pathology

The two hallmarks of the Alzheimer disease pathology are 1) extracellular plaque deposits of the amyloid beta peptide and 2) flame-shaped neurofibrillary tangles of the microtubule-binding protein tau. The production and deposition of the amyloid beta peptide appear to play a central role in the pathogenesis of Alzheimer disease and form the basis of the amyloid cascade hypothesis.

Amyloid plaques are easily visible on routine hematoxylin and eosin (H and E) staining. These are extracellular and can be stained with special amyloid stains like Thioflavin-S or Congo Red. Under polarized light, they show characteristic apple-green birefringence typical for an amyloid protein.

Biochemical and Genetic Pathology

Amyloid beta peptide is a 42-amino acid peptide and derives from the precursor protein, amyloid beta precursor protein (APP). The amyloid beta precursor protein is a transmembrane glycoprotein that spans the membrane once. The gene for amyloid beta precursor protein is on chromosome 21. Amyloid beta precursor protein is cleaved by beta-secretase, and gamma secretase to release amyloid beta peptide containing 40 or 42 amino acids, denoted as Ab 1-40 or Ab1-42, respectively. Beta secretase act on amyloid beta precursor proteins to produce the N terminal and gamma secretase produce the C terminal of the peptide. The peptide Ab 1-42, which is the main pathogenic peptide, is highly hydrophobic and tends to aggregate into oligomers and fibrils. The hydrophobic amino acids confer the hydrophobicity in the C terminal of the peptide. These fibrils then arrange in a beta-pleated sheet and form the amyloid plaques seen on conventional H and E staining or amyloid specific staining. Recent research suggests that the oligomers rather than the amyloid plaques are neurotoxic and may major play a role in pathogenesis.[4][5]

Several clinical and genetic observations support the amyloid cascade hypothesis. One of the initial observations of early-onset Alzheimer disease identified a genetic link to the disease. Patients with Down syndrome have an extra copy of chromosome 21 and, by inference, have excess amyloid beta precursor protein production. Most patients with Down syndrome have amyloid plaques in their brains by age 30 and clinically develop Alzheimer disease dementia in their 40s, suggesting a role for excess amyloid beta precursor protein or its processing in Alzheimer disease. Mutations in the amyloid beta precursor protein gene itself, one of the first studied in familial Alzheimer disease, account for 10% to 15% of familial Alzheimer disease. Another mutation in the catalytic subunits of the gamma-secretase complex, the enzyme involved in processing amyloid beta precursor protein to an amyloid beta peptide, also causes familial Alzheimer disease. Presenilin 1 and 2 are the subunits of the enzyme gamma secretase complex. Mutation in Presenilin 1 gene is the commonest cause of familial Alzheimer disease. The gene for Presenilin 1 is located on chromosome 14 and accounts for up to 80% of cases of familial Alzheimer disease. Researchers think that this mutation causes excess production of Ab 1-42 as opposed to Ab 1-40. The gene for Presenilin 2 is on chromosome 1.

Another well-established and supporting genetic risk factor for the amyloid cascade hypothesis is Apolipoprotein E (ApoE) polymorphism. There are three isoforms of the protein in the population encoded by the gene for ApoE; these are ApoE2, ApoE3, and ApoE4. Carriers with polymorphism ApoE4 have a higher risk of sporadic Alzheimer disease as compared to the general population. The risk is also higher in those with homozygous ApoE4 as compared to heterozygous ApoE4 suggesting a dose-dependent risk. Studies have shown a robust correlation with ApoE4 gene carrier status and amyloid plaque burden in both patients with Alzheimer disease and cognitively normal individuals. Among the many functions, ApoE acts as a chaperone involved in the clearance of amyloid plaques, and the ApoE4 isoform appears to be a poor chaperone promoting amyloid beta deposition.[6][7][8]

Mechanisms

The normal function of the amyloid beta peptide is not known. Mechanisms exist in the human brain to degrade the amyloid beta peptide. Despite this, a faction of this may remain in the brain, which is transported out of the human brain across the blood-brain barrier. An imbalance in these pathways appears to lead to the accumulation of the peptide. Recent research suggests that amyloid beta oligomers are more important in the pathogenesis than the plaques. These oligomers are thought to induce synaptic dysfunction, disrupt neural connectivity, and neuronal death.[9][10]

Clinicopathologic Correlations

Although amyloid beta plaques are pathognomonic of Alzheimer disease pathology, there is no strong correlation of amyloid beta plaque burden, spatiotemporal distribution, and Alzheimer disease severity. It is possible, however, that the total amyloid plaque burden increases as Alzheimer disease progresses. In contrast, the spatiotemporal distribution of tau neurofibrillary tangles follows a predictable pattern, with neurofibrillary tangles seen in the entorhinal cortex and hippocampus and gradually spreading to involve other areas, with primary motor, sensory and visual areas involved in the last stages of Alzheimer disease.

Clinical Significance

Amyloid plaque burden and spatial distribution of the plaques are now visible on imaging. A radiotracer called Pittsburgh Compound B is FDA approved for use in PET scan for the diagnosis of Alzheimer disease. This molecule preferentially targets and binds to amyloid beta plaques with high affinity and specificity and can estimate the plaque burden and distribution of Alzheimer disease. This imaging is now in use in almost all clinical trials of Alzheimer disease.

Free amyloid peptide levels are measurable in cerebrospinal fluid (CSF) and plasma. Low levels of amyloid beta, perhaps an indicator of low clearance from the brain, and abnormally high tau protein in CSF serve as biomarkers of Alzheimer disease in clinical trials.

Amyloid Beta as Therapeutic Target

Several clinical trials using immunotherapy have attempted to decrease plaque burden as a mechanism to stop the progression of Alzheimer disease. However, most of these trials failed to meet the primary endpoint or were stopped due to safety concerns. Typically, vaccination against the amyloid beta or passive immunization with antibodies targeted against amyloid peptide was the attempted intervention. The failure of these therapies may argue against the central role of amyloid deposition in Alzheimer disease. However, it is possible that the treatments were tested in the later stages of the disease rather than early in the disease process when the impact on disease modification could be higher. Alternatively, this approach does not address the tau protein pathway in the disease and hence could not affect disease progression.

Teaching Points

The amyloid precursor protein is processed to form an amyloid beta peptide. An imbalance in production and clearing of the peptide appears to lead to the formation of excess amyloid oligomers and amyloid plaques. The latter is the histopathological hallmarks of Alzheimer disease.

The gene for amyloid precursor protein is located on chromosome 21 and encodes a transmembrane protein. The amyloid precursor protein is cleaved by beta-secretase and gamma-secretase to release the amyloid beta peptide. Genetic mutation of the amyloid precursor protein gene or the catalytic subunits of the gamma-secretase complex, for example, Presenilin 1 and Presenilin 2, cause familial Alzheimer disease.

Mutation in amyloid precursor protein was the first to be discovered, but a mutation in Presenilin 1 is the most common cause (up to 80%) of familial Alzheimer disease.

Familial Alzheimer disease characteristically presents with early-onset dementia, onset before age 60 years, and usually autosomal dominant inheritance pattern.

Apo E4 carrier status confers a high risk for sporadic Alzheimer disease. This risk is dose-dependent with homozygous status conferring higher risk.

Low CSF amyloid beta peptide and high CSF Tau peptides are biomarkers in a clinical trial setting.

Chemical compounds, for example, Pittsburgh Compound B, that bind the amyloid plaque, can be used as imaging biomarkers.