miR-154-5p Is a Novel Endogenous Ligand for TLR7 Inducing Microglial Activation and Neuronal Injury.

Toll-like receptors (TLRs) are a collection of pattern recognition sensors that form a first line of defence by detecting pathogen- or damage-associated molecular patterns and initiating an inflammatory response. TLR activation in microglia, the major immune cells in the brain, can trigger the release of inflammatory molecules, which may contribute to various CNS diseases including Alzheimer's disease. Recently, some microRNAs were shown to serve as signalling molecules for TLRs. Here, we present miR-154-5p as a novel TLR7 ligand. Exposing microglia to miR-154-5p results in cytokine release and alters expression of the TLR signalling pathway dependent on TLR7. Additionally, miR-154-5p causes neuronal injury in enriched cortical neuron cultures and additive toxicity in the presence of microglia. Finally, intrathecal injection of miR-154-5p into mice leads to neuronal injury and accumulation of microglia in the cerebral cortex dependent on TLR7 expression. In conclusion, this study establishes miR-154-5p as a direct activator of TLR7 that can cause neuroinflammation and neuronal injury, which may contribute to CNS disease.

Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.

Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.

Sex differences in hippocampal ß-amyloid accumulation in the triple-transgenic mouse model of Alzheimer's disease and the potential role of local estrogens.

Introduction: Epidemiological studies show that women have a higher prevalence of Alzheimer's disease (AD) than men. Peripheral estrogen reduction during aging in women is proposed to play a key role in this sex-associated prevalence, however, the underlying mechanism remains elusive. We previously found that transcription factor early growth response-1 (EGR1) significantly regulates cholinergic function. EGR1 stimulates acetylcholinesterase (AChE) gene expression and is involved in AD pathogenesis. We aimed to investigate whether the triple-transgenic AD (3xTg-AD) mice harboring PS1 M146V , APP Swe , and Tau P301L show sex differences in ß-amyloid (Aß) and hyperphosphorylated tau (p-Tau), the two primary AD hallmarks, and how local 17ß-estradiol (E2) may regulate the expression of EGR1 and AChE. Methods: We first sacrificed male and female 3xTg-AD mice at 3-4, 7-8, and 11-12 months and measured the levels of Aß, p-Tau, EGR1, and AChE in the hippocampal complex. Second, we infected SH-SY5Y cells with lentivirus containing the amyloid precursor protein construct C99, cultured with or without E2 administration we measured the levels of extracellular Aß and intracellular EGR1 and AChE. Results: Female 3xTg-AD mice had higher levels of Aß compared to males, while no p-Tau was found in either group. In SH-SY5Y cells infected with lentivirus containing the amyloid precursor protein construct C99, we observed significantly increased extracellular Aß and decreased expression of intracellular EGR1 and AChE. By adding E2 to the culture medium, extracellular Aß(l-42) was significantly decreased while intracellular EGR1 and AChE expression were elevated. Discussion: This data shows that the 3xTg-AD mouse model can be useful for studying the human sex differences of AD, but only in regards to Ap. Furthermore, in vitro data shows local E2 may be protective for EGR1 and cholinergic functions in AD while suppressing soluble Aß(1-42) levels. Altogether, this study provides further in vivo and in vitro data supporting the human epidemiological data indicating a higher prevalence of AD in women is related to changes in brain estrogen levels.

Nigral neuropathology of Parkinson's motor subtypes coincide with circuitopathies: a scoping review.

The neuropathological substrates of Parkinson's disease (PD) patients with motor subtypes tremor-dominance (TD), non-tremor dominance (nTD), postural instability and gait difficulty (PIGD), and akinetic-rigid (AR) are not completely differentiated. While extensive pathological research has been conducted on neuronal tissue of PD patients, data have not been discussed in the context of mechanistic circuitry theories differentiating motor subtypes. It is, therefore, expected that a more specific and tailored management of PD symptoms can be accomplished by understanding symptom-specific neuropathological mechanisms with the detail histology can provide. This scoping review gives an overview of the literature comparing TD and nTD PD motor subtypes by clarify observed pathology with underlying physiological circuitry theories. Studies using an array of pathological examination techniques have shown significant differences between TD and nTD PD subtypes. nTD PD patients show higher neuronal loss, gliosis, extraneuronal melanin deposits, and neuroaxonal dystrophy in multiple subregions of the substantia nigra (SN) related to the overactivity of the indirect motor loop. TD patients show more severe cell loss specifically in medial SN subdivisions, and have damage in the retrorubral field A-8 that projects to the dorsolateral striatum and ventromedial thalamus in the direct motor loop. Pathological studies are consistent with neuroimaging data and support contemporary mechanistic circuitry theories of PD motor symptom genesis. Further multimodal neuroimaging and histological studies are required to validate and expand upon these findings.

Sex differences in the neuropathological hallmarks of Alzheimer's disease: focus on cognitively intact elderly individuals.

AIMS: Women are more vulnerable to Alzheimer's disease (AD) than men. We investigated (i) whether and at what age the AD hallmarks, that is, ß-amyloid (Aß) and hyperphosphorylated Tau (p-Tau) show sex differences; and (ii) whether such sex differences may occur in cognitively intact elderly individuals. METHODS: We first analysed the entire post-mortem brain collection of all non-demented 'controls' and AD donors from our Brain Bank (245 men and 403 women), for the presence of sex differences in AD hallmarks. Second, we quantitatively studied possible sex differences in Aß, Aß42 and p-Tau in the entorhinal cortex of well-matched female (n = 31) and male (n = 21) clinically cognitively intact elderly individuals. RESULTS: Women had significantly higher Braak stages for tangles and amyloid scores than men, after 80 years. In the cognitively intact elderly, women showed higher levels of p-Tau, but not Aß or Aß42, in the entorhinal cortex than men, and a significant interaction of sex with age was found only for p-Tau but not Aß or Aß42. CONCLUSIONS: Enhanced p-Tau in the entorhinal cortex may play a major role in the vulnerability to AD in women.

Risk Reduction and Prevention of Alzheimer's Disease: Biological Mechanisms of Diet.

Alzheimer's Disease (AD) incidence is increasing and with no disease modifying agents available, preventative measures through lifestyle factors are being investigated. Combined with the prevention of AD risk factors such as heart disease, diabetes, and with more recent evidence, microbiome dysfunction, there is a substantial foundation for diet as a modifiable risk factor and preventative measure for AD. Recent evidence suggests AD associated pathologies, such as oxidative stress and inflammation, can be modulated by the lipids, vitamins, and polyphenols obtained through nutritional intake. Furthermore, epidemiological and preclinical evidence has uncovered certain compounds within foods that may have beneficial effects in the prevention of AD, including omega-3 fatty acids, vitamin E, and resveratrol among others. However, clinical data examining specific compounds are often inconsistent and fail to replicate the preclinical data. On the other hand, dietary patterns such as the Mediterranean or MIND diet have shown promise in terms of clinical outcomes for patients, indicating a reductionist approach to diet is not as effective as a holistic dietary pattern. In this review, we summarize some of the biological mechanisms of key compounds in their relation to AD and how they fit into a dietary pattern that supports the role of diet as a risk reducing factor for AD.

Prevention and Treatment of Alzheimer's Disease: Biological Mechanisms of Exercise.

Alzheimer's disease (AD) is the most common form of dementia. With an aging population and no disease modifying treatments available, AD is quickly becoming a global pandemic. A substantial body of research indicates that lifestyle behaviors contribute to the development of AD, and that it may be worthwhile to approach AD like other chronic diseases such as cardiovascular disease, in which prevention is paramount. Exercise is an important lifestyle behavior that may influence the course and pathology of AD, but the biological mechanisms underpinning these effects remain unclear. This review focuses on how exercise can modify four possible mechanisms which are involved with the pathology of AD: oxidative stress, inflammation, peripheral organ and metabolic health, and direct interaction with AD pathology. Exercise is just one of many lifestyle behaviors that may assist in preventing AD, but understanding the systemic and neurobiological mechanisms by which exercise affects AD could help guide the development of novel pharmaceutical agents and non-pharmacological personalized lifestyle interventions for at-risk populations.