overview: The brains of cognitively healthy older adults have similar amounts of soluble nonfibrillar amyloid protein as the brains of Alzheimer’s disease patients. The findings challenge the long-held theory that having higher levels of amyloid protein is the underlying cause of Alzheimer’s disease.
sauce: USC
New research from the USC Leonard Davis School of Gerontology challenges existing ideas about how accumulation of a protein called amyloid beta (Aβ) in the brain is linked to Alzheimer’s disease.
Accumulation of amyloid protein is associated with Alzheimer’s disease-related neurodegeneration, but little is known about how this protein is associated with normal brain aging, said the senior author of the study. said University Professor Caleb Finch, holder of the 2000 ARCO/William F. Kieschnick Chair. Neurobiology of Aging, USC Leonard Davis School.
To investigate levels of Aβ in the human brain, researchers analyzed tissue samples from both healthy brains and brains of people with dementia. More severe Alzheimer’s disease cases were indicated by higher Braak staging scores, which measure how prevalent signs of Alzheimer’s disease are in the brain.
The analysis revealed that older, cognitively healthy brains displayed similar amounts of soluble nonfibrillar amyloid protein as brains from Alzheimer’s disease patients. However, as researchers expected, the brains of Alzheimer’s patients had higher amounts of insoluble Aβ fibrils, a form of amyloid protein that aggregate to form the distinct ‘plaques’ seen in Alzheimer’s disease. Max Thorwald, lead author and postdoc on the study, said. Researcher at USC Leonard Davis School.
The findings challenge the idea that high amounts of amyloid protein in general are the underlying cause of Alzheimer’s disease, say Finch and Thorwald. Although it may not be disease-specific and may be general age-related changes in the brain, higher levels of fibrillar amyloid appear to be a better indicator of poor brain health. am.
Rather than simply Alzheimer’s disease being associated with increased production of Aβ protein, a more important issue may be the diminished ability to effectively clear the protein and halt the formation of fibrillar amyloid, which contributes to plaque formation. said Thorwald.
“These findings further support the use of aggregated or fibrillar amyloid as biomarkers for the treatment of Alzheimer’s disease,” said Thorwald. “At sites where amyloid processing occurs, there are fewer precursors and enzymes available for processing, which may suggest amyloid clearance as a key problem in Alzheimer’s disease.”
Increased amyloid levels occur in early adulthood and vary by brain region. Further studies, including studies investigating drugs that may disrupt amyloid, have incorporated positron emission tomography (PET) imaging in both healthy individuals and patients with Alzheimer’s disease of a wide range of ages to demonstrate that amyloid processing and removal may occur over time. We need to determine how and where it changes in the brain over time. , he added.
“The brain’s frontal cortex has more amyloid production compared to the cerebellum during the aging process of the human brain, which is consistent with Alzheimer’s disease-associated pathology in later life.” Thorwald said.
“Future projects could both modulate amyloid processing or clear amyloid via monoclonal antibodies currently used in clinical trials for the treatment of Alzheimer’s disease, in both cognitively normal and Alzheimer’s disease patients. We need to look at amyloid over the lifetime of the patient.”
A monoclonal antibody treatment, lemanecab, has been observed to reduce Aβ plaques in clinical trials and was recently approved by the FDA for the potential to slow cognitive decline in people with Alzheimer’s disease. needs to do more careful research on long-term effects, Finch said.
“Lecanemab clearly works to reduce fibrillar amyloid,” he said. “However, major side effects, such as brain swelling and bleeding, were 100% greater in him than in the control group, and delayed effects and potential effects are unknown.”
Learning more about how the brain processes and clears proteins such as Aβ may provide important insights into Alzheimer’s disease and its causes. Finch noted that few cases of dementia have amyloid plaques, or aggregated clumps of her Aβ protein, as the only pathology present in the brains of affected patients.
Instead, most cases show more complex tissue abnormalities, from accumulation of additional types of proteins to small hemorrhages in the brain. “The aging brain is a jungle”.
The study, “Future of Amyloid in the Growing Pathology of Brain Aging and Dementia,” was published online December 19, 2022 in the journal. Alzheimer’s disease and dementiaIn addition to Finch and Thorwald, Justin Silva and Elizabeth Head of the University of California, Irvine are co-authors.
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sauce: USC
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See also
Original research: open access.
“The future of amyloid in brain aging and the pathological spread of dementia” By Max A. Thorwald et al. Alzheimer’s disease and dementia
overview
The future of amyloid in brain aging and the pathological spread of dementia
Positron emission tomography (PET) imaging studies in Alzheimer’s disease (AD) patients show a progressive increase in fibrillar Aβ-amyloid. We analyzed soluble Aβ in AD and controls, as the current PET ligand underestimates the non-fibrillar morphology.
To identify the mechanisms responsible for soluble Aβ in AD brains, we examined lipid rafts (LR) where amyloid precursor protein (APP) is enzymatically processed.
The frontal cortex was compared with the cerebellum with minimal AD pathology. Elevations of soluble Aβ40 and Aβ42 were similar in mid- and late-stage AD (Braak 2-3 and 4-6) compared to cognitively normal controls (CTL; Braak 0-1).
Clinical-grade AD showed greater increases in soluble Aβ40 than Aβ42 compared to CTL. LR raft yield per gram of AD frontal cortex was 20% lower than controls, whereas cerebellar LR had no difference in Braak score. The extensive overlap of soluble Aβ levels in AD controls contrasts with the PET findings for fibrillar Aβ.
These findings further support fibrillar Aβ as a biomarker for AD treatment and indicate the need for a more detailed postmortem analysis of diverse soluble and insoluble Aβ aggregates associated with PET.
