Effects of MDMA on neuroplasticity, amyloid burden and phospho-tau expression in APPswe/PS1dE9 mice

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is still one of the most consumed drugs by adolescents. Its abuse is related with cognitive impairment, which seems due to maladaptive plasticity and neural stress. In turn, new hypotheses suggest that Alzheimer’s disease (AD) may be promoted by neural stressors. Aims and methods: To test if there is an increase in vulnerability to AD after chronic MDMA consumption, we investigated the effects of this drug on recognition memory and its neurotoxic and neuroplastic effects in a transgenic mouse model of presymptomatic familiar AD (APP/PS1 dE9, Tg). Results: MDMA-treated animals showed recognition memory deficits, regardless of genotype, which were accompanied by changes in plasticity markers. Tg mice showed an impaired expression of Arc compared with wild-type animals, but exposure to MDMA induced an increase in the expression of this factor of the same percentage in both genotypes. However, the expression of c-fos, BDNF and p-CREB was not significantly altered by MDMA treatment in Tg mice. Although Tg mice had higher free choline levels than wild-type mice (about 123%), MDMA did not modify these levels in any case, ruling out any specific effect of this drug on the acetylcholine pathway. MDMA treatment significantly increased the presence of cortical amyloid plaques, as well as Aβ40, Aβ42 and secreted APPβ levels in Tg mice. These plaques were accompanied by increased tau phosphorylation (S199), which does not seem to occur via the canonic pathway involving AKT, CDK5 or GSK3β. Conclusions: The present results support previous evidences that MDMA can contribute to the amyloid cascade.

Download Full-text

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice

10.1101/2020.08.18.254649 ◽

2020 ◽

Author(s):

Mickael Audrain ◽

Jean-Vianney Haure-Mirande ◽

Justyna Mleczko ◽

Minghui Wang ◽

Jennifer K. Griffin ◽

...

Keyword(s):

Late Onset ◽

Amyloid Β ◽

Tau Phosphorylation ◽

Amyloid Burden ◽

Wild Type ◽

Sporadic Alzheimer’S Disease ◽

Stab Injury ◽

Microglial Phenotype ◽

Important Regulator

ABSTRACTMicroglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimer’s disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPTP301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E (Apoe) transcription was upregulated in MAPTP301S mice overexpressing TYROBP and transcription of genes previously associated with Apoe, including Axl, Ccl2, Tgfβ and Il6, was altered in both APP/PSEN1 and MAPTP301S mice overexpressing TYROBP. Lastly, Tyrobp and Apoe mRNAs were clearly increased in Trem2-null mice in microglia recruited around a cortical stab injury or amyloid-β (Aβ) deposits. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype.

Download Full-text

Naphthalene Monoimide Derivative Ameliorates Amyloid Burden and Cognitive Decline in a Transgenic Mouse Model of Alzheimer's Disease

Advanced Therapeutics ◽

10.1002/adtp.202000225 ◽

2021 ◽

pp. 2000225

Author(s):

Sourav Samanta ◽

Kolla Rajasekhar ◽

Madhu Ramesh ◽

Natarajan Arul Murugan ◽

Shadab Alam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Cognitive Decline ◽

Transgenic Mouse ◽

Transgenic Mouse Model ◽

Amyloid Burden ◽

Model Of Alzheimer’S Disease

Download Full-text

Bilateral inactivation of medial temporal structures (MT) is required to induce recognition memory deficits

Clinical Neurophysiology ◽

10.1016/j.clinph.2006.07.292 ◽

2007 ◽

Vol 118 (5) ◽

pp. e175

Author(s):

G. Alarcón ◽

M.E. Lacruz ◽

J.J. García Seoane ◽

A. Valentín ◽

C.D. Binnie ◽

...

Keyword(s):

Recognition Memory ◽

Memory Deficits ◽

Temporal Structures

Download Full-text

Lithium Reduces Tau Phosphorylation but Not Aβ or Working Memory Deficits in a Transgenic Model with Both Plaques and Tangles

American Journal Of Pathology ◽

10.2353/ajpath.2007.061178 ◽

2007 ◽

Vol 170 (5) ◽

pp. 1669-1675 ◽

Cited By ~ 133

Author(s):

Antonella Caccamo ◽

Salvatore Oddo ◽

Lana X. Tran ◽

Frank M. LaFerla

Keyword(s):

Working Memory ◽

Memory Deficits ◽

Tau Phosphorylation ◽

Transgenic Model

Download Full-text

Icariin Decreases the Expression of APP and BACE-1 and Reduces the β-amyloid Burden in an APP Transgenic Mouse Model of Alzheimer's Disease

International Journal of Biological Sciences ◽

10.7150/ijbs.6232 ◽

2014 ◽

Vol 10 (2) ◽

pp. 181-191 ◽

Cited By ~ 39

Author(s):

Lan Zhang ◽

Cong Shen ◽

Jin Chu ◽

Ruyi Zhang ◽

Yali Li ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Transgenic Mouse ◽

Transgenic Mouse Model ◽

Amyloid Burden ◽

Model Of Alzheimer’S Disease ◽

Β Amyloid ◽

Bace 1

Download Full-text

Fecal Microbiota Transplantation Decreases Amyloid Load and Improves Cognition in Alzheimer’s

10.1101/687376 ◽

2019 ◽

Author(s):

Shalini Elangovan ◽

Thomas J Borody ◽

R M Damian Holsinger

Keyword(s):

Alzheimer’S Disease ◽

Recognition Memory ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Therapeutic Effects ◽

Wild Type ◽

Neuroprotective Effects ◽

Amyloid Pathology ◽

Amyloid Load ◽

Old Mice

AbstractThe efficacy of fecal microbiota transplantation (FMT) in Alzheimer’s disease has yet to be investigated. Here, we show that FMT is capable of providing neuroprotective effects in two groups of treated 5xFAD Alzheimer’s mice, old transgenic (Tg) mice fed fecal slurry from healthy, wild-type donors of similar age (Old Tg-FO) and old mice fed fecal slurry from younger healthy, wild-type donors (Old Tg-FY). Improved spatial and recognition memory in Old Tg-FY and enhanced recognition memory in Old Tg-FO were observed when compared to Old Tg-Control mice given saline. Crucially, there was significant decreases in cortical Aβ loading in all treated mice, demonstrating the therapeutic effects of FMT in improving cognition and reducing amyloid pathology in AD brains.One Sentence SummaryFecal microbial transplants reduce amyloid pathology and improve cognition in Alzheimer’s mice.

Download Full-text