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Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice.

ABSTRACT: Accumulation of amyloid-? (A?) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer's disease (AD). After almost 15 years from their generation, 3xTg-AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg-AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed A? and tau load, neuroinflammation, and cognitive changes in 2-, 6-, 12-, and 20-month-old female 3xTg-AD and nontransgenic (NonTg) mice. We found that ~80% of the mice analyzed had A? plaques in the caudal hippocampus at 6 months of age, while 100% of them had A? plaques in the hippocampus at 12 months of age. Cortical A? plaques were first detected at 12 months of age, including in the entorhinal cortex. Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6-month-old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age. Neuroinflammation was first evident in 6-month-old mice and increased as a function of age. These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6 months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD-like pathology in female 3xTg-AD mice, and will facilitate the design of future studies using these mice.

SUBMITTER: Belfiore R

PROVIDER: S-EPMC6351836 | biostudies-other | 2019 Feb

REPOSITORIES: biostudies-other

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Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice.

Belfiore Ramona R Rodin Alexis A Ferreira Eric E Velazquez Ramon R Branca Caterina C Caccamo Antonella A Oddo Salvatore S

Aging cell 20181128 1

Accumulation of amyloid-β (Aβ) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer's disease (AD). After almost 15 years from their generation, 3xTg-AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg-AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed Aβ and tau load, neuroinfla ...[more]

PMID: 30488653

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Project description:Epidemiological studies have found that heavy alcohol use is associated with increased risk for Alzheimer's disease (AD), with frequent drinking earlier in adulthood increasing risk. The increases in neuroinflammation featured in both heavy alcohol use and AD may be partially responsible for this link. However, it is unknown if abstinence mitigates this risk. We hypothesized that binge ethanol during mid adult life would persistently increase AD pathology even after prolonged abstinence. Male and female 3xTg-AD mice (APPSwe, tauP301, Psen1tm1Mpm) which feature progressive amyloid (Aβ) and tau pathology, received chronic binge ethanol (5g/kg/day, 5-days-on/2-days-off, i.g.) or water during adulthood (from 5.5 to 9 months of age), followed by abstinence and assessment at 14 months of age. The effects of ethanol on protective AD genes (e.g., APOE and TREM2) as well as proinflammatory genes were measured by PCR. Levels of pathologic tau and Aβ were measured by immunohistochemistry and western blot. Ethanol caused persistent reductions in protective AD genes: APOE (25% reduction, *p < 0.05), TREM2 (28%, *p < 0.05), LPL (40%, ** p < 0.01), and CTSD (24%, *p < 0.05) and promoted a proinflammatory gene signature in female, but not male cortex. Concurrently, ethanol increased total and hyperphosphorylated tau (AT8) in piriform cortex and hippocampus of females, but not males. Levels of AT8 were negatively correlated with APOE (R = -0.67, *p < 0.05) and TREM2 (R = -0.78, **p < 0.005) suggesting protective roles in pathogenesis. No differences were found in levels of main regulators of tau phosphorylation state (GSK3β, PKA, PP2A), suggesting ethanol disrupted clearance of tau. Therefore, we measured the effect of ethanol on lysosomes, which degrade tau, and lysosomal localization of tau using co-immunofluorescence. In females, ethanol caused a persistent reduction in mature LAMP1 lysosomes in CA1 of hippocampus (35%, *p < 0.05), along with a 60% increase in total tau (*p < 0.05). Thus, chronic binge ethanol during mid adult life causes a persistent enhancement of tau pathology in cortical and hippocampal brain regions of females. Persistent AD pathology was associated with an increased proinflammatory signature and a reduction of mature lysosomes. This implicates binge ethanol exposure with increased risk of AD pathologic progression in females.

Dataset Information

Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice.

Publications

Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice.

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