Increased tau phosphorylation follows impeded dopamine clearance in a P301L and novel P301L/COMT‐deleted (DM) tau mouse model

Koppel, Jeremy; Jimenez, Heidy; Adrien, Leslie R.; Chang, Eric H.; Malhotra, Anil K.; Davies, Peter

doi:10.1111/jnc.14593

Cited by 15 publications

(31 citation statements)

References 35 publications

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“…Tau pathology has also been suggested to be facilitated by alterations to the LC-NA system as demonstrated in rodents (7). Moreover, whilst no significant relationship between NA/MHPG and tau was observed in our analyses, MHPG more than NA may be related to p-tau as animal studies have shown that NA Omethylation in MHPG is necessary for tau spreading (78).…”

Section: More Studies Are Required To Determine the Relationship Between Brain Pathology And Csf Na/mhpg Biomarkerscontrasting

confidence: 43%

CSF and PET biomarkers for noradrenergic dysfunction in neurodegenerative diseases: a systematic review and meta-analysis

Lancini

Haag

Bartl³

et al. 2021

Preprint

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The noradrenergic system shows pathological modifications in aging and neurodegenerative diseases and is thought to be affected in the early stages of both Alzheimer and Parkinson's diseases. We conducted a meta-analysis of noradrenergic differences in Alzheimer's disease type dementia (ADD) and Parkinson's disease (PD) using CSF and PET biomarkers. CSF noradrenaline (NA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) as well as NA transporter availability (PET MeNER) levels in controls, ADD and PD patients was summarized from 26 articles (1025 patients and 839 controls in total) using a random-effects model meta-analysis. Compared with controls, PD patients showed significant reductions in CSF NA and MHPG, and PET MeNER binding in the hypothalamus. In ADD, MHPG levels were increased compared with controls. Age correlated with CSF MHPG levels in ADD, but not in PD. Noradrenergic dysfunction in neurodegenerative diseases can be detected using CSF or PET measures and may be more pronounced in PD compared to ADD.

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Section: More Studies Are Required To Determine the Relationship Between Brain Pathology And Csf Na/mhpg Biomarkerscontrasting

confidence: 43%

CSF and PET biomarkers for noradrenergic dysfunction in neurodegenerative diseases: a systematic review and meta-analysis

Lancini

Haag

Bartl³

et al. 2021

Preprint

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“…Recently, the novel P301L(+/+)/ COMT(−/−) (DM) mouse, fashioned as a hyperdopaminergic tau mouse model of psychotic AD, was observed to have an increased frontal dopamine surge in response to catecholamine reuptake inhibition relative to COMT competent P301L mice. Moreover, the increase in dopamine was associated with an increase in tau phosphorylation, recapitulating an established pathologic correlate of psychosis in AD (104). Another recent effort looked to model the synaptic pathology of psychosis in AD.…”

Section: Examples Of Novel Animal Models Of Psychosis In Admentioning

confidence: 89%

Animal Models of Psychosis in Alzheimer Disease

Krivinko

Koppel

Savonenko³

et al. 2020

The American Journal of Geriatric Psychiatry

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Psychosis in Alzheimer Disease (AD) represents a distinct clinicopathologic variant associated with increased cognitive and functional morbidity and an accelerated disease course. To date, extant treatments offer modest benefits with significant risks. The development of new pharmacologic treatments for psychosis in AD would be facilitated by validated preclinical models with which to test candidate interventions. The current review provides a brief summary of the process of validating animal models of human disease together with a critical analysis of the challenges posed in attempting to apply those standards to AD-related behavioral models. An overview of phenotypic analogues of human cognitive and behavioral impairments, with an emphasis on those relevant to psychosis, in AD-related mouse models is provided, followed by an update on recent progress in efforts to translate findings in the pathophysiology of psychotic AD into novel models. Finally, some future directions are suggested to expand the catalogue of psychosis-relevant phenotypes that may provide a sturdier framework for model development and targets for preclinical treatment outcomes.

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“…Interestingly, a SNP associated with increased DAT1 expression [30] is predictive of higher brain atrophy and associated with increased dementia [31]. Though recent data suggest that dopamine surges in the extracellular space increase ptau [32], the physiological relevance of tau‐induced increased levels of DAT1 in the context of AD‐type amyloidosis will need further study. Loss in Trem2 function underlies neurodegenerative pathology in AD and is associated with a specific microglial phenotype associated with neuritic changes in amyloid models [20].…”

Section: Discussionmentioning

confidence: 99%

Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation

Koller

Ibanez

et al. 2021

Neuropathology Appl Neurobio

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Aims To illuminate the pathological synergy between Aβ and tau leading to emergence of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), here, we have performed a comparative neuropathological study utilising three distinctive variants of human tau (WT tau, P301L mutant tau and S320F mutant tau). Previously, in non‐transgenic mice, we showed that WT tau or P301L tau does not form NFT while S320F tau can spontaneously aggregate into NFT, allowing us to test the selective vulnerability of these different tau conformations to the presence of Aβ plaques. Methods We injected recombinant AAV‐tau constructs into neonatal APP transgenic TgCRND8 mice or into 3‐month‐old TgCRND8 mice; both cohorts were aged 3 months post injection. This allowed us to test how different tau variants synergise with soluble forms of Aβ (pre‐deposit cohort) or with frank Aβ deposits (post‐deposit cohort). Results Expression of WT tau did not produce NFT or altered Aβ in either cohort. In the pre‐deposit cohort, S320F tau induced Aβ plaque deposition, neuroinflammation and synaptic abnormalities, suggesting that early tau tangles affect the amyloid cascade. In the post‐deposit cohort, contemporaneous expression of S320F tau did not exacerbate amyloid pathology, showing a dichotomy in Aβ‐tau synergy based on the nature of Aβ. P301L tau produced NFT‐type inclusions in the post‐deposit cohort, but not in the pre‐deposit cohort, indicating pathological synergy with pre‐existing Aβ deposits. Conclusions Our data show that different tau mutations representing specific folding variants of tau synergise with Aβ to different extents, depending on the presence of cerebral deposits.

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Increased tau phosphorylation follows impeded dopamine clearance in a P301L and novel P301L/COMT‐deleted (DM) tau mouse model

Cited by 15 publications

References 35 publications

CSF and PET biomarkers for noradrenergic dysfunction in neurodegenerative diseases: a systematic review and meta-analysis

CSF and PET biomarkers for noradrenergic dysfunction in neurodegenerative diseases: a systematic review and meta-analysis

Animal Models of Psychosis in Alzheimer Disease

Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation

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