Summary: The brains of cognitively healthy older people contain similar amounts of soluble, nonfibrillar amyloid proteins as the brains of people with Alzheimer’s disease. The findings challenge the long-held theory that having higher levels of amyloid protein is an underlying cause of Alzheimer’s disease.
Source: USC
A new study from the USC Leonard Davis School of Gerontology challenges existing ideas about how the buildup of a protein called beta-amyloid (Aβ) in the brain is linked to Alzheimer’s disease.
While amyloid protein buildup has been linked to Alzheimer’s disease-related neurodegeneration, little is known about how the protein is linked to normal brain aging, said university professor Caleb Finch. , lead author of the study and holder of the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging at the USC Leonard Davis School.
To explore Aβ levels in the human brain, the researchers analyzed tissue samples from both healthy brains and brains from patients with dementia. More severe Alzheimer’s cases were indicated by higher Braak staging scores, a measure of the extent of detection of signs of Alzheimer’s pathology in the brain.
The analysis revealed that older, cognitively healthy brains had similar amounts of soluble nonfibrillar amyloid protein as the brains of patients with Alzheimer’s disease. But, as the researchers expected, the brains of Alzheimer’s patients had higher amounts of insoluble Aβ fibrils, the form of amyloid protein that clumps together to form the telltale “plaques” seen in disease, said Max Thorwald, the study’s first author and postdoctoral researcher. researcher at the USC Leonard Davis School.
The findings challenge the idea that simply having higher amounts of amyloid protein in general is an underlying cause of Alzheimer’s disease, say Finch and Thorwald. Instead, the increase in soluble Aβ may be a general age-related change in the brain not specific to Alzheimer’s disease, while higher levels of fibrillar amyloid appear to be a better indicator of poor brain health.
Rather than Alzheimer’s disease simply involving increased production of Aβ protein, the more important problem may be a reduced ability to effectively remove the protein and prevent the creation of plaque-contributing fibrillar amyloid, Thorwald said.
“These findings further support the use of aggregate or fibrillar amyloid as a biomarker for Alzheimer’s disease treatments,” Thorwald said. “The site where amyloid processing occurs has fewer precursors and enzymes available for processing, which may suggest that amyloid clearance is a key issue in Alzheimer’s disease.”
Increases in amyloid levels occur in early adulthood and differ by brain region. Further studies, including those of drugs that can break down amyloid, should incorporate positron emission tomography (PET) imaging in healthy individuals and patients with Alzheimer’s disease. a wide range of ages to determine how and where amyloid processing and clearance changes in the brain over time. , he added.
“The frontal cortex of the brain produces more amyloid than the cerebellum during the aging process of the human brain, which coincides with their pathologies correlated with Alzheimer’s disease in later life,” Thorwald said.
“Future projects should examine amyloid across the lifespan in cognitively normal patients and patients with Alzheimer’s disease with both modulation of amyloid processing or amyloid clearance by monoclonal antibodies currently used in clinical trials for the treatment of Alzheimer’s disease.”
The monoclonal antibody treatment lemanecab has been observed to reduce Aβ plaques in clinical trials and recently received FDA approval for its potential to slow cognitive decline in patients with Alzheimer’s disease. Alzheimer’s, but the findings warrant further research into the long-term impact, Finch said.
“Lecanemab clearly works to decrease fibrillar amyloid,” he said. “However, we are concerned about major side effects, including brain swelling and bleeding, which were 100% greater than in controls, with unknown delayed or latent impact.”
Knowing more about how the brain processes and eliminates proteins such as Aβ could provide important information about Alzheimer’s disease and its causes. Finch noted that very few cases of dementia occur with amyloid plaques, or masses of aggregated Aβ protein, as the only pathology present in the brains of affected patients.
Instead, most cases present with more complicated tissue abnormalities, ranging from the accumulation of additional types of protein to small bleeds in the brain: “The aging brain is a jungle.”
The study, “The Future of Amyloid in the Expanding Pathology of Brain Aging and Dementia,” was published online December 19, 2022 in the journal Alzheimer’s and dementia. Besides Finch and Thorwald, co-authors include Justine Silva and Elizabeth Head of the University of California, Irvine.
About this Alzheimer’s disease research news
Author: Press office
Source: USC
Contact: Press office – USC
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Original research: Free access.
“The Future of Amyloid in the Expanding Pathology of Brain Aging and Dementia” by Max A. Thorwald et al. Alzheimer’s and dementia
Summary
The future of amyloid in the expanding pathology of brain aging and dementia
Positron emission tomography (PET) imaging studies of patients with Alzheimer’s disease (AD) show progressive increases in fibrillar Aβ amyloid. Since current PET ligands underestimate non-fibrillar forms, we assayed soluble Aβ in AD and controls.
To identify the mechanisms responsible for soluble Aβ in AD brains, we examined lipid rafts (LRs), where amyloid precursor protein (APP) is enzymatically processed.
The frontal cortex was compared to the cerebellum, which has minimal AD pathology. Compared to cognitively normal controls (CTL; Braak 0-1), elevations of soluble Aβ40 and Aβ42 were similar for mid- and later-stage AD (Braak 2-3 and 4-6).
Clinical grade AD showed a greater increase in soluble Aβ40 than Aβ42 compared to CTL. The yield of LR raft per gram of AD frontal cortex was 20% lower than controls, while cerebellar LR did not differ in Braak score. The significant overlap of soluble Aβ levels in controls with AD contrasts with PET findings on fibrillar Aβ.
These findings further support fibrillar Aβ as a biomarker for AD treatments and show the need for more detailed post-mortem analysis of various soluble and insoluble Aβ aggregates compared to PET.
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