Long-term continuous allopregnanolone elevation causes memory decline and hippocampus shrinkage, in female wild-type B6 mice

Bengtsson, Sara K.; Johansson, Monika; Bäckström, Torbjörn

doi:10.1016/j.yhbeh.2015.10.010

Cited by 13 publications

(13 citation statements)

References 59 publications

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“…The positive GABA A receptor modulating steroid allopregnanolone (APα) is currently in a phase II trial (NCT04838301). In a single dose, APα was shown to reduce Aβ generation and to promote regeneration of neurons and restore learning and memory in a 3×Tg mouse model of AD [185,186], but the chronic treatment caused memory decline in wild-type mice and accelerated dementia in selected AD mice models [187,188]. Interestingly, APα affects microglial morphology and phagocytic function, which might potentially contribute to its beneficial effect in AD [189].…”

Section: Therapeutic Compounds Affecting Glutamate/gaba Neurotransmission In Microglial-neuron Communicationmentioning

confidence: 99%

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Czapski

Strosznajder

2021

IJMS

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The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer’s disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of microglial receptors regulates the immunological response of these cells, which in AD could be neuroprotective or neurotoxic. The novel research approaches revealed the complexity of microglial function, including the interplay with other cells during neuroinflammation and in the AD brain. The purpose of this review is to describe the role of several proteins and multiple receptors on microglia and neurons, and their involvement in a communication network between cells that could lead to different metabolic loops and cell death/survival. Our review is focused on the role of glutamatergic, GABAergic signaling in microglia–neuronal cross-talk in AD and neuroinflammation. Moreover, the significance of AD-related neurotoxic proteins in glutamate/GABA-mediated dialogue between microglia and neurons was analyzed in search of novel targets in neuroprotection, and advanced pharmacological approaches.

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Section: Therapeutic Compounds Affecting Glutamate/gaba Neurotransmission In Microglial-neuron Communicationmentioning

confidence: 99%

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Czapski

Strosznajder

2021

IJMS

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“…Acute administration of ALLO improves memory function in one mouse model of AD (197), but other studies using rodent models suggest that chronic exposure to ALLO may actually cause memory deficits and exacerbate disease-related functional impairments (198–200). The observation that ALLO transiently increases CREB phosphorylation and increases indicators of neurogenesis in wildtype rats (201) suggests that the acute and chronic effects may not be the same.…”

Section: Neurosteroids and Memory Functionmentioning

confidence: 99%

Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders

2019

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Memory dysfunction is a symptomatic feature of many neurologic and neuropsychiatric disorders; however, the basic underlying mechanisms of memory and altered states of circuitry function associated with disorders of memory remain a vast unexplored territory. The initial discovery of endogenous neurosteroids triggered a quest to elucidate their role as neuromodulators in normal and diseased brain function. In this review, based on the perspective of our own research, the advances leading to the discovery of positive and negative neurosteroid allosteric modulators of GABA type-A (GABA A ), NMDA, and non-NMDA type glutamate receptors are brought together in a historical and conceptual framework. We extend the analysis toward a state-of-the art view of how neurosteroid modulation of neural circuitry function may affect memory and memory deficits. By aggregating the results from multiple laboratories using both animal models for disease and human clinical research on neuropsychiatric and age-related neurodegenerative disorders, elements of a circuitry level view begins to emerge. Lastly, the effects of both endogenously active and exogenously administered neurosteroids on neural networks across the life span of women and men point to a possible underlying pharmacological connectome by which these neuromodulators might act to modulate memory across diverse altered states of mind.

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“…Nonselective blockage or modulation of these two receptors could protect cognitive impairment, making them innovative feasible therapeutic agents for AD [ 49 ]. Hippocampus, a brain region important for memory, learning, and neurogenesis [ 50 , 51 , 52 ], is one of the earliest affected brain regions that tends to exhibit the most rapid volume loss in the disease progression, and its pathology was found to be central to AD [ 50 , 53 , 54 ].…”

Section: Introductionmentioning

confidence: 99%

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Ejaz

Wang

Lang

2020

IJMS

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Alzheimer’s disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals’ roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions’ current status in several AD features, and some conflicting reports are present herein.

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Long-term continuous allopregnanolone elevation causes memory decline and hippocampus shrinkage, in female wild-type B6 mice

Cited by 13 publications

References 59 publications

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

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