Temporal Characterization of the Amyloidogenic APPswe/PS1dE9;hAPOE4 Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aß) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers (APOE4) compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aß immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human APOE4 gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human APOE3 gene (APOE ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aß deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, APOE4 carriers showed elevated Aß, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to APOE3 carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.

Systemic Inflammation Causes Microglial Dysfunction With a Vascular AD phenotype.

Background: Studies in rodents and humans have indicated that inflammation outside CNS (systemic inflammation) affects brain homeostasis contributing to neurodevelopmental disorders. Itis becoming increasingly evident that such early insults may also belinked to neurodegenerative diseases like late-onset Alzheimer's disease (AD). Importantly, lifestyle and stress, such as viral or bacterial infection causing chronic inflammation, may contribute to neurodegenerative dementia. Systemic inflammatory response triggers a cascade of neuroinflammatory responses, altering brain transcriptome, cell death characteristic of AD, and vascular dementia. Our study aimed to assess the temporal evolution of the pathological impact of systemic inflammation evoked by prenatal and early postnatal peripheral exposure of viral mimetic Polyinosinic:polycytidylic acid (PolyI:C) and compare the hippocampal transcriptomic changes with the profiles of human post-mortem AD and vascular dementia brain specimens. Methods: We have engineered the PolyI:C sterile infection model in wildtype C57BL6 mice to achieve chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months, and 16 months), taking the hippocampus as a reference brain region, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD, and Controls (CTL), in parallel to Vascular dementia (VaD) patients' specimens. Results: We found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological shifts progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression throughout aging, with a peak in differential expression at 9 months. We show that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows the reproducibility of some gene targets in vascular dementia specimens as compared to AD ones. Conclusions: The PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation causes progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling, and the loss of neuronal functionality seen to some extent in human AD and Vascular dementia suggesting early immune insults could be crucial in neurodegenerative diseases.

Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aß antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5-6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics.

Classifying dementia progression using microbial profiling of saliva.

INTRODUCTION: There is increasing evidence linking periodontal infections to Alzheimer's disease (AD). Saliva sampling can reveal information about the host and pathogen interactions that can inform about physiological and pathological brain states. METHODS: A cross-sectional cohort of age-matched participants (78) was segmented according to their chemosensory (University of Pennsylvania Smell Identification Test; UPSIT) and cognitive scores (Mini-Mental State Exam; MMSE and clinical dementia rating; CDR). Mid-morning saliva was sampled from each participant and processed for microbiome composition and cytokine analysis. Linear discriminant analysis (LDA) was used to unravel specific changes in microbial and immunological signatures and logistic regression analysis (LRA) was employed to identify taxa that varied in abundance among patient groups. RESULTS: Using olfaction we distinguish in the cognitively normal population a segment with high chemosensory scores (CNh, 27) and another segment with chemosensory scores (CNr, 16) as low as mild cognitive impairment (MCI, 21) but higher than the AD group (17). We could identify stage-specific microbial signatures changes but no clearly distinct cytokine profiles. Periodontal pathogen species as Filifactor villosus decline with the increasing severity of AD, whereas opportunistic oral bacteria such as Leptotrichia wadei show a significant enrichment in MCI. CONCLUSIONS: The salivary microbiome indicates stage-dependent changes in oral bacteria favoring opportunistic species at the expense of periodontal bacteria, whereas the inflammatory profiles remain mainly unchanged in the sampled population.

Linking mechanisms of periodontitis to Alzheimer's disease.

PURPOSE OF REVIEW: The review article discusses the association between periodontal disease and the development of dementia. RECENT FINDINGS: In the last decade, increasing evidence has pointed to a microbial and inflammatory origin for Alzheimer's disease with the discovery of oral and airway bacteria, viruses, and fungal species in the brain of patients with Alzheimer's disease. Furthermore, recognized as the culprit of neural network dysfunction, ß-amyloid oligomeric species have antimicrobial properties reinforcing the idea that dysbiosis in the host-microbiota interaction can be at the origin of dementia. Periodontitis (gum disease), a persistent low-grade inflammatory condition, caused by pathogenic microorganisms, has been linked to an increased ß-amyloid burden and cognitive disabilities later in life. SUMMARY: The pathogens of periodontal disease and the subsequent chronic inflammatory responses have significant implications on the development of Alzheimer's disease. The exact molecular mechanism by which Porphyromonas gingivalis and periodontal disease are involved in the pathogenicity of Alzheimer's disease is not currently evident. Understanding this causality can be instrumental in the development of treatments for this yet uncurable disease.

Olfactory dysfunction in the pathophysiological continuum of dementia.

Sensory capacities like smell, taste, hearing, vision decline with aging, but increasing evidence show that sensory dysfunctions are one of the early signs diagnosing the conversion from physiological to pathological brain state. Smell loss represents the best characterized sense in clinical practice and is considered as one of the first preclinical signs of Alzheimer's and Parkinson's disease, occurring a decade or more before the onset of cognitive and motor symptoms. Despite the numerous scientific reports and the adoption in clinical practice, the etiology of sensory damage as prodromal of dementia remains largely unexplored and more studies are needed to resolve the mechanisms underlying sensory network dysfunction. Although both cognitive and sensory domains are progressively affected, loss of sensory experience in early stages plays a major role in reducing the autonomy of demented people in their daily tasks or even possibly contributing to their cognitive decline. Interestingly, the chemosensory circuitry is devoid of a blood brain barrier, representing a vulnerable port of entry for neurotoxic species that can spread to the brain. Furthermore, the exposure of the olfactory system to the external environment make it more susceptible to mechanical injury and trauma, which can cause degenerative neuroinflammation. In this review, we will summarize several findings about chemosensory impairment signing the conversion from healthy to pathological brain aging and we will try to connect those observations to the promising research linking environmental influences to sporadic dementia. The scientific body of knowledge will support the use of chemosensory diagnostics in the presymptomatic stages of AD and other biomarkers with the scope of finding treatment strategies before the onset of the disease.

Progressive signaling changes in the olfactory nerve of patients with Alzheimer's disease.

Olfaction declines with aging and appears to be a prodromal sign of cognitive decline in progressive neurodegenerative diseases. Nevertheless, very little is known about the pathophysiological changes underlying smell loss that may reflect early network dysfunction. A cross-sectional histoanatomical study was conducted on postmortem olfactory nerves of patients with increasing severity of dementia from mild cognitive impairment (MCI) to moderate and severe Alzheimer's disease. The olfactory bulbs and tracts show a prominent and progressive tauopathy in contrast to a weaker amyloid pathology localized to the glomerular region. Topological analysis of Notch signaling components reveals a transient increase in Jagged1 expression in mitral cells of the olfactory bulb of patients with MCI and a gradual decline onwards. Analysis of the olfactory tract reveals an abundance of corpora amylacea, which declines starting from the MCI stage. With the increasing severity of dementia, corpora amylacea are characterized by a gradual shift in cytoskeletal proteins, tau, MAP2 and glial fibrillary acid protein, as well as by a decrease in their Reelin and Jagged1 content. Our research indicates that the olfactory nerve undergoes early and sequential morphological and signaling alterations that correlate with the development of dementia suggesting that this structure may capture and propagate neuronal network imbalances to connected higher brain centers of the entorhinal cortex and hippocampus.

Effects of Monoamines and Antidepressants on Astrocyte Physiology: Implications for Monoamine Hypothesis of Depression.

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders affecting over one-fifth of the population worldwide. Owing to our limited understanding of the pathophysiology of MDD, the quest for finding novel antidepressant drug targets is severely impeded. Monoamine hypothesis of MDD provides a robust theoretical framework, forming the core of a large jigsaw puzzle, around which we must look for the vital missing pieces. Growing evidence suggests that the glial loss observed in key regions of the limbic system in depressed patients, at least partly, accounts for the structural and cognitive manifestations of MDD. Studies in animal models have subsequently hinted at the possibility that the glial atrophy may play a causative role in the precipitation of depressive symptoms. Antidepressants as well as monoamine neurotransmitters exert profound effects on the gene expression and metabolism in astrocytes. This raises an intriguing possibility that the astrocytes may play a central role alongside neurons in the behavioral effects of antidepressant drugs. In this article, we discuss the gene expression and metabolic changes brought about by antidepressants in astrocytes, which could be of relevance to synaptic plasticity and behavioral effects of antidepressant treatments.