Tau and amyloid-related pathologies in the entorhinal cortex have divergent effects in the hippocampal circuit

Angulo, Sergio; Orman, Rena; Neymotin, Samuel A.; Liu, L.; Buitrago, Luna; Cepeda-Prado, Efraín; Stefanov, Dimitre; Lytton, William W.; Stewart, Mark; Small, Scott A.; Duff, Karen; Moreno, Herman

doi:10.1016/j.nbd.2017.08.015

Cited by 53 publications

(61 citation statements)

References 96 publications

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“…Animals were anesthetized via i. p. injection with keta‐ mine/xylazine (100/10 mg/kg). The brain was placed in a cold cutting solution bubbled with O 2 /CO 2 95/5%, following methods described in previous studies . Horizontal ventral brain slices and recording conditions have also been reported before .…”

Section: Methodsmentioning

confidence: 99%

“…The brain was placed in a cold cutting solution bubbled with O 2 /CO 2 95/5%, following methods described in previous studies . Horizontal ventral brain slices and recording conditions have also been reported before . Neurons were located at an approximate position: AP −3.8 mm, medio‐lateral 3.0 mm, and dorso‐ventral −5.6 mm.…”

Section: Methodsmentioning

confidence: 99%

“…The link between specific brain region susceptibility and the pathophysiology of AD is not well understood. In early AD, the subiculum is affected by the amyloidogenic pathology, which includes decreased number of neurons, dendritic loss, and neuronal hypersynchrony . The subiculum is involved in memory retrieval and spatial memory …”

Section: Introductionmentioning

confidence: 99%

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Amyloid pathology‐produced unexpected modifications of calcium homeostasis in hippocampal subicular dendrites

Angulo

Henzi

Neymotin

et al. 2020

Alzheimer's & Dementia

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Introduction: Alzheimer's disease (AD) is linked to neuronal calcium dyshomeostasis, which is associated with network hyperexcitability. Decreased expression of the calcium-binding protein cal-bindin-D 28K (CB) might be a susceptibility factor for AD.The subiculum is affected early in AD, for unknown reasons. Methods:In AD, CB knock-out and control mice fluorescence Ca 2+ imaging combined with patch clamp were used to characterize Ca 2+ dynamics, resting Ca 2+ , and Ca 2+buffering capacity in subicular neurons. CB expression levels in wild-type and AD mice were also analyzed. Results:The subiculum and dentate gyrus of wild-type mice showed age-related decline in CB expression not observed in AD mice. Resting Ca 2+ and Ca 2+ -buffering capacity was increased in aged AD mice subicular dendrites. Modeling suggests that AD calcium changes can be explained by alterations of Ca 2+ extrusion pumps rather than by buffers. Discussion:Overall, abnormal Ca 2+ homeostasis in AD has an age dependency that comprises multiple mechanisms, including compensatory processes.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Amyloid pathology‐produced unexpected modifications of calcium homeostasis in hippocampal subicular dendrites

Angulo

Henzi

Neymotin

et al. 2020

Alzheimer's & Dementia

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“…These data suggest that the accumulation of tau in this model does not strongly impact EC neuronal activity by 16-months in vivo. However, the absence of an observed hTau impact in EC should be carefully interpreted, as EC-hTau expression has been linked to hypometabolism in ~9-month mice 39 and has recently been shown to blunt Aβ-associated hyperexcitability in vitro 38 . It is possible then that detection of hTau-mediated effects on neuronal activity are partly dependent on the sensitivity of the assays used to measure them.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence suggests that hAPP/Aβ expression can facilitate the movement and progression of tau pathology along the entorhinal cortexhippocampal (EC-HIPP) network, and that tau-mediated axonal pathology and cell loss are exacerbated by Aβ accumulation 36,37 . Altered EC excitability and metabolic dysfunction are also associated with Aβ and tau pathology within this network 38,39 . Importantly, these effects differ from those found in mice exhibiting only one hallmark pathological state (either hAPP/Aβ or tau pathology).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of entorhinal cortex hyperactivity reduces Aβ and tau pathology

Rodriguez

Barrett

Duff

2018

Preprint

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13High levels of the amyloid-beta (Aβ) peptide have been shown to disrupt neuronal function and 14 induce hyperexcitability, but it is unclear what effects Aβ-associated hyperexcitability may have 15 on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to 16 model the impact of hAPP/Aβ accumulation on tauopathy in the entorhinal cortex-hippocampal 17(EC-HIPP) network, we demonstrate that hAPP aggravates EC tau aggregation and accelerates 18 pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for 19 hAPP/Aβ, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta 20 rhythmicity. Chronic chemogenetic attenuation of Aβ-associated hyperactivity led to reduced 21 hAPP/Aβ accumulation and reduced pathological tau spread into downstream hippocampus. 22These data strongly support the hypothesis that in Alzheimer's disease (AD), Aβ-associated 23 hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, 24and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD 25 pathology in vivo. 26 Results 84 Aβ-associated acceleration of tau pathology in EC-Tau/hAPP mice in vivo 85Overexpression of mutant hAPP (Swedish/Indiana) in the hAPP/J20 mouse line leads to progressive 86Aβ plaque deposition throughout the hippocampus and neocortex, contributing to aberrant 87 network activity and cognitive deficits (21, 22). To test whether Aβ pathology alters the 88 progression of tau pathology along the EC-HIPP circuit, we generated the hAPP/J20 x EC-Tau 89 mouse line, hereafter referred to as EC-Tau/hAPP (described in Methods). At 16-months, EC-90Tau/hAPP mice exhibit robust amyloid deposition throughout the EC and HIPP using 6E10 91( Figure 1B), with no change in Aβ deposition compared to age-matched hAPP mice sampled. 92Diffuse amyloid accumulation made up the majority of the pathology, though small, compact Aβ 93 plaques and large, dense-core Aβ plaques were also present (arrows, Figure 1B). Mice 94 expressing hTau alone (EC-Tau) did not exhibit 6E10 immunoreactivity ( Figure 1A). 95Immunostaining for MC1 revealed a dramatic increase in abnormal, misfolded tau within the 96 somatodendritic compartments of EC and HIPP neurons of EC-Tau/hAPP mice compared to 97 EC-Tau littermates ( Figure 1C-D). This increase was over three-fold higher in EC cells (EC-98 Tau/hAPP: 131.00 ± 19.38 vs EC-Tau: 40.52 ± 7.24) and over ten-fold higher in DG granule 99 cells (EC-Tau/hAPP: 359.20 ± 109.40 vs EC-Tau: 30.67 ± 14.88) ( Figure 1E), suggesting that 100 hAPP/Aβ expression in the EC-HIPP network accelerates tau pathology along the classical 101 perforant pathway. MC1 immunostaining in 10-month EC-Tau/hAPP mice revealed mostly 102 diffuse tau in neuropil throughout the EC and in axons terminating in the middle-and outer-103 molecular layers of the DG ( Figure 1F). No somatodendritic MC1+ staining was detected in 104HIPP subregions at this age. By 16-months, it was clear that tau aggregation had not ...

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Factors Affecting Resilience and Prevention of Alzheimer's Disease and Related Dementias

Masurkar,

Marsh,

Morgan

et al. 2024

Annals of Neurology

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Alzheimer's disease (AD) is a devastating, age‐associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ‐targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD‐related pathologies, such as NFTs, are not directly targeted. A non‐mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD‐related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024

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Tau and amyloid-related pathologies in the entorhinal cortex have divergent effects in the hippocampal circuit

Cited by 53 publications

References 96 publications

Amyloid pathology‐produced unexpected modifications of calcium homeostasis in hippocampal subicular dendrites

Amyloid pathology‐produced unexpected modifications of calcium homeostasis in hippocampal subicular dendrites

Attenuation of entorhinal cortex hyperactivity reduces Aβ and tau pathology

Factors Affecting Resilience and Prevention of Alzheimer's Disease and Related Dementias

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