Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

Neuner, Sarah M.; Hohman, Timothy J.; Richholt, Ryan; Bennett, David A.; Schneider, Julie A.; Jager, Philip L. De; Huentelman, Matthew J.; O’Connell, Kathryn A; Kaczorowski, Catherine C.

doi:10.1101/225714

Cited by 8 publications

(14 citation statements)

References 59 publications

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“…When including genotype and BXD background strain, PLD3 remained predictive of learning acquisition speed (β = 0.04, p = 0.003) but not when modeling fear memory recall (β = 0.085, p = 0.08). These findings are unsurprising as the main effect for the AD-BXD behavioral stratification was observed upon learning acquisition slope rather than memory recall, as recall is more strongly sensitive to β-amyloid burden [ 14 , 15 ]. Collectively, these human and animal data suggest that PLD3 expression is linked to cognition in the aged brain.…”

Section: Resultsmentioning

confidence: 99%

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease

et al. 2021

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Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer’s disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition.

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Section: Resultsmentioning

confidence: 99%

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease

et al. 2021

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“…In 5xFAD mice, females also show more AD‐related pathology than males, including increased Aβ‐plaque load, and elevated levels of APP and Aβ‐42 as early as 4‐6 months of age (Sadleir et al, 2015) . These sex differences cannot simply be attributed to differences in transgene expression, given similar levels of hAPP and hPS1 mRNA have been observed in male and female 5xFAD mice …”

Section: Discussionmentioning

confidence: 99%

“…31 These sex differences cannot simply be attributed to differences in transgene expression, given similar levels of hAPP and hPS1 mRNA have been observed in male and female 5xFAD mice. 49 Previous studies documenting motor dysfunction in 5xFAD mice have used only one sex of 5xFAD mice, 22,24 and this is the first study to examine sex differences in motor impairments. Consistent with previous studies, we reliably detected motor impairment in both male and female 5xFAD mice, and found that age-related progression of motor impairment was generally consistent across sexes.…”

Section: Are There Sex Differences In the Progression Of The Motor mentioning

confidence: 99%

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

O’Leary

Mantolino

Stover

et al. 2018

Genes Brain and Behavior

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Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf im on motor function, suggesting that Dysf im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.

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“…When including genotype (β-amyloid state) and BXD background strain, PLD3 remained predictive of learning acquisition speed (β=0.04, p=0.003) but not when modeling fear memory recall (β=0.085, p=0.08). These findings are unsurprising as the main effect for the AD-BXD behavioral stratification was observed upon learning acquisition slope rather than memory recall, as memory recall is more strongly sensitive to β-amyloid burden 17,20 . Collectively, these human and animal data suggest that PLD3 expression has a direct impact upon cognition in the aged brain.…”

Section: Pld3 Mrna Levels Are Lower In Ad-bxd Mice and Correlated Witmentioning

confidence: 99%

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease

Nackenoff

Hohman

Neuner

et al. 2019

Preprint

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PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease ABSTRACT Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer's disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to determine whether PLD3 is relevant to memory and cognition in sporadic AD, to observe its distribution in normal human brain and AD-affected brain, to describe its subcellular localization, and to evaluate its molecular function. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both βamyloid pathology and cognition.

show abstract

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

Cited by 8 publications

References 59 publications

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease

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