Amyloid-β (Aβ) peptides are produced from the regulated intramembrane proteolysis of the amyloid precursor protein (APP). Sequential proteolytic cleavage events by β- and γ-secretase generate Aβ peptides of varying lengths, including Aβ40 and Aβ42. Its two extra hydrophobic residues give Aβ42 a higher propensity to aggregate into soluble oligomers and insoluble deposits than Aβ40 or the range of shorter peptides that have been observed in recent years by mass spectrometry analysis of cerebral spinal fluid (CSF). Multiple aggregated forms exist, from dimers to β-pleated sheet fibrils in compact neuritic plaques, but a primary toxic species, or its mechanism of neuronal toxicity, has not been definitively identified.

Mutations linked to familial Alzheimer’s disease generally exert pathogenic effects by increasing overall Aβ levels and/or the Aβ42:Aβ40 ratio. Aβ clearance—by way of enzymes, transport along the brain’s vasculature, or microglial phagocytosis—is thought to decrease with aging or as a result of interaction with other genetic risk factors for AD.

Excess amounts of Aβ can induce a variety of pathologic processes. Aβ can impair neuronal and glial function, synaptic physiology, neurotransmission, and cognition. Evidence points to transcellular spread and templated seeding, and the resulting deposition of aggregated Aβ into extraneuronal amyloid plaques is a pathological hallmark of AD.

Aβ reduction in the CSF starts more than a decade before symptoms; this is a biomarker of AD and clinical-grade CSF assays are being developed. The FDA has approved two positron emission tomography (PET) tracers for the detection of brain amyloid burden during life, but the lack of insurance reimbursement limits their use. Animal models of Aβ amyloidosis respond to therapy with small-molecule and immunotherapy drugs, but these findings have been only partially borne out in human trials. As of yet, no anti-amyloid approach has achieved clinical benefit to support FDA approval.

References

Alzpedia Citations

1. APP

Further Reading