Guam ALS-PDC is a distinct double-prion disorder featuring both tau and Aβ prions

Abstract

The amyotrophic lateral sclerosis–parkinsonism dementia complex (ALS-PDC) of Guam is an endemic neurodegenerative disease that features widespread tau tangles, occasional α-synuclein Lewy bodies, and sparse β-amyloid (Aβ) plaques distributed in the central nervous system. Extensive studies of genetic or environmental factors have failed to identify a cause of ALS-PDC. Building on prior work describing the detection of tau and Aβ prions in Alzheimer’s disease (AD) and Down syndrome brains, we investigated ALS-PDC brain samples for the presence of prions. We obtained postmortem frozen brain tissue from 26 donors from Guam with ALS-PDC or no neurological impairment and 71 non-Guamanian donors with AD or no neurological impairment. We employed cellular bioassays to detect the prion conformers of tau, α-synuclein, and Aβ proteins in brain extracts. In ALS-PDC brain samples, we detected high titers of tau and Aβ prions, but we did not detect α-synuclein prions in either cohort. The specific activity of tau and Aβ prions was increased in Guam ALS-PDC compared with sporadic AD. Applying partial least squares regression to all biochemical and prion infectivity measurements, we demonstrated that the ALS-PDC cohort has a unique molecular signature distinguishable from AD. Our findings argue that Guam ALS-PDC is a distinct double-prion disorder featuring both tau and Aβ prions.

Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) features CTE-like tau seeds in brain and spinal cord

“…The presence of tau seeds in ALS/PDC brain (frontal cortex) is in agreement with published data (43). To our knowledge, this is the first demonstration of seeding-competent tau in the spinal cord.…”

“…We report here on the seeding behavior of tau in Guam ALS/PDC, a neurodegenerative disorder of unknown cause that was previously highly prevalent in the Pacific Island of Guam (Mariana Islands). In agreement with a recent publication (43), we found that Guam ALS/PDC brain samples display robust tau seeding activity in tau biosensor cells. Notably, we also detected strong tau seeding activity in spinal cord tissue.…”

“…Further, we found that 2 out of 8 Guam non-neurological control subjects also showed seeding activity in the biosensor cells. This is in keeping with seeding data from another study (43) and with previous neuropathological findings in Guamanians, i.e., tau pathology appears to be a frequent background feature in the Guam population (32, 33). A plausible explanation is that these tissues represent presymptomatic cases.…”

“…Of note, the tau seeding activity may have been limited by tissue availability, as only 3.5 μg of tissue per well in a 96-well plate were used for seeding in the biosensors. The presence of tau seeds in ALS/PDC brain (frontal cortex) is in agreement with published data (43). To our knowledge, this is the first demonstration of seeding-competent tau in the spinal cord.…”

“…Tau seeds in all evaluated tissues showed a strong preference for the 4R/4R tau biosensors. This preference was also observed in the aforementioned study on tau seeds in Guam ALS/PDC (43). CTE tau appears to also seed preferably onto 4R/4R biosensors (48).…”

Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) features CTE-like tau seeds in brain and spinal cord

“…The presence of tau seeds in ALS/PDC brain (frontal cortex) is in agreement with published data (43). To our knowledge, this is the first demonstration of seeding-competent tau in the spinal cord.…”

“…We report here on the seeding behavior of tau in Guam ALS/PDC, a neurodegenerative disorder of unknown cause that was previously highly prevalent in the Pacific Island of Guam (Mariana Islands). In agreement with a recent publication (43), we found that Guam ALS/PDC brain samples display robust tau seeding activity in tau biosensor cells. Notably, we also detected strong tau seeding activity in spinal cord tissue.…”

“…Further, we found that 2 out of 8 Guam non-neurological control subjects also showed seeding activity in the biosensor cells. This is in keeping with seeding data from another study (43) and with previous neuropathological findings in Guamanians, i.e., tau pathology appears to be a frequent background feature in the Guam population (32, 33). A plausible explanation is that these tissues represent presymptomatic cases.…”

“…Of note, the tau seeding activity may have been limited by tissue availability, as only 3.5 μg of tissue per well in a 96-well plate were used for seeding in the biosensors. The presence of tau seeds in ALS/PDC brain (frontal cortex) is in agreement with published data (43). To our knowledge, this is the first demonstration of seeding-competent tau in the spinal cord.…”

“…Tau seeds in all evaluated tissues showed a strong preference for the 4R/4R tau biosensors. This preference was also observed in the aforementioned study on tau seeds in Guam ALS/PDC (43). CTE tau appears to also seed preferably onto 4R/4R biosensors (48).…”

Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) features CTE-like tau seeds in brain and spinal cord

“…The presence of tau seeds in ALS/PDC brain (frontal cortex) is in agreement with published data (43). To our knowledge, this is the first demonstration of seeding-competent tau in the spinal cord.…”

“…We report here on the seeding behavior of tau in Guam ALS/PDC, a neurodegenerative disorder of unknown cause that was previously highly prevalent in the Pacific Island of Guam (Mariana Islands). In agreement with a recent publication (43), we found that Guam ALS/PDC brain samples display robust tau seeding activity in tau biosensor cells. Notably, we also detected strong tau seeding activity in spinal cord tissue.…”

“…Further, we found that 2 out of 8 Guam non-neurological control subjects also showed seeding activity in the biosensor cells. This is in keeping with seeding data from another study (43) and with previous neuropathological findings in Guamanians, i.e., tau pathology appears to be a frequent background feature in the Guam population (32, 33). A plausible explanation is that these tissues represent presymptomatic cases.…”

“…Of note, the tau seeding activity may have been limited by tissue availability, as only 3.5 μg of tissue per well in a 96-well plate were used for seeding in the biosensors. The presence of tau seeds in ALS/PDC brain (frontal cortex) is in agreement with published data (43). To our knowledge, this is the first demonstration of seeding-competent tau in the spinal cord.…”

“…Tau seeds in all evaluated tissues showed a strong preference for the 4R/4R tau biosensors. This preference was also observed in the aforementioned study on tau seeds in Guam ALS/PDC (43). CTE tau appears to also seed preferably onto 4R/4R biosensors (48).…”

Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) features CTE-like tau seeds in brain and spinal cord

“…The presence of tau seeds in ALS/PDC brain (frontal cortex) is in agreement with published data (43). To our knowledge, this is the first demonstration of seeding-competent tau in the spinal cord.…”

“…We report here on the seeding behavior of tau in Guam ALS/PDC, a neurodegenerative disorder of unknown cause that was previously highly prevalent in the Pacific Island of Guam (Mariana Islands). In agreement with a recent publication (43), we found that Guam ALS/PDC brain samples display robust tau seeding activity in tau biosensor cells. Notably, we also detected strong tau seeding activity in spinal cord tissue.…”

“…Further, we found that 2 out of 8 Guam non-neurological control subjects also showed seeding activity in the biosensor cells. This is in keeping with seeding data from another study (43) and with previous neuropathological findings in Guamanians, i.e., tau pathology appears to be a frequent background feature in the Guam population (32, 33). A plausible explanation is that these tissues represent presymptomatic cases.…”

“…Of note, the tau seeding activity may have been limited by tissue availability, as only 3.5 μg of tissue per well in a 96-well plate were used for seeding in the biosensors. The presence of tau seeds in ALS/PDC brain (frontal cortex) is in agreement with published data (43). To our knowledge, this is the first demonstration of seeding-competent tau in the spinal cord.…”

“…Tau seeds in all evaluated tissues showed a strong preference for the 4R/4R tau biosensors. This preference was also observed in the aforementioned study on tau seeds in Guam ALS/PDC (43). CTE tau appears to also seed preferably onto 4R/4R biosensors (48).…”