Age-dependent cognitive decline and amygdala pathology in α-synuclein transgenic mice

As the life expectancy continues to increase, the cognitive decline associated with Alzheimer’s disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of “microglia aging.” This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

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Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712648115 ◽

2018 ◽

Vol 115 (7) ◽

pp. 1635-1640 ◽

Cited By ~ 24

Author(s):

Yulan Xiong ◽

Stewart Neifert ◽

Senthilkumar S. Karuppagounder ◽

Qinfang Liu ◽

Jeannette N. Stankowski ◽

...

Keyword(s):

Transgenic Mice ◽

Molecular Mechanisms ◽

Model Development ◽

Behavioral Deficits ◽

Lrrk2 G2019s ◽

Age Dependent ◽

Dependent Cell ◽

A Cell ◽

Mutant Lrrk2 ◽

Familial Parkinson’S Disease

Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson’s disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons. Accompanying the loss of DA neurons are DA-dependent behavioral deficits and α-synuclein pathology that are also LRRK2 GS kinase-dependent. Transmission EM reveals that that there is an LRRK2 GS kinase-dependent significant reduction in synaptic vesicle number and a greater abundance of clathrin-coated vesicles in DA neurons. These transgenic mice indicate that LRRK2-induced DA and NE neurodegeneration is kinase-dependent and can occur in a cell-autonomous manner. Moreover, these mice provide a substantial advance in animal model development for LRRK2-associated PD and an important platform to investigate molecular mechanisms for how DA neurons degenerate as a result of expression of mutant LRRK2.

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Age-Dependent Cognitive Deficits and Neuronal Apoptosis in Cyclooxygenase-2 Transgenic Mice

Journal of Neuroscience ◽

10.1523/jneurosci.21-20-08198.2001 ◽

2001 ◽

Vol 21 (20) ◽

pp. 8198-8209 ◽

Cited By ~ 154

Author(s):

Katrin I. Andreasson ◽

Alena Savonenko ◽

Sveta Vidensky ◽

Joseph J. Goellner ◽

Yan Zhang ◽

...

Keyword(s):

Transgenic Mice ◽

Cognitive Deficits ◽

Neuronal Apoptosis ◽

Cyclooxygenase 2 ◽

Age Dependent

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APOE genotype regulates pathology and disease progression in synucleinopathy

Science Translational Medicine ◽

10.1126/scitranslmed.aay3069 ◽

2020 ◽

Vol 12 (529) ◽

pp. eaay3069 ◽

Cited By ~ 17

Author(s):

Albert A. Davis ◽

Casey E. Inman ◽

Zachary M. Wargel ◽

Umber Dube ◽

Brittany M. Freeberg ◽

...

Keyword(s):

Substantia Nigra ◽

Transgenic Mice ◽

Cognitive Decline ◽

Apolipoprotein E ◽

Motor Performance ◽

Apoe Genotype ◽

Amyloid Β ◽

Tau Pathology ◽

Increased Risk ◽

Over Time

Apolipoprotein E (APOE) ε4 genotype is associated with increased risk of dementia in Parkinson’s disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. APOE ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, APOE ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that APOE ε4 exacerbates pathology, and suggest that APOE ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.

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