The gut microbiome controls reactive astrocytosis during Aβ amyloidosis via propionate-mediated regulation of IL-17.

Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in a male APPPS1-21 AD mouse model. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown.

Gut microbiome-derived metabolites in Alzheimer's disease: Regulation of immunity and potential for therapeutics.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and cause of dementia. Despite the prevalence of AD, there is a lack of effective disease modifying therapies. Recent evidence indicates that the gut microbiome (GMB) may play a role in AD through its regulation of innate and adaptive immunity.

The role of the gut microbiome in the regulation of astrocytes in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is the most common cause of dementia. AD is characterized pathologically by proteinaceous aggregates composed of amyloid beta (Aβ) and tau as well as progressive neurodegeneration. Concurrently with the buildup of protein aggregates, a strong neuroinflammatory response, in the form of reactive astrocytosis and microgliosis, occurs in the AD brain.

The gut microbiome regulates astrocyte reaction to Aβ amyloidosis through microglial dependent and independent mechanisms.

Background: Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aβ) plaques and proinflammatory microglial phenotype in male APPPS1-21 mice. However, the effect of GMB perturbation on astrocyte phenotypes and microglial-astrocyte communication in the context of amyloidosis has not been examined.

Methods: To study whether the GMB modulates astrocyte phenotype in the context of amyloidosis, APPPS1-21 male and female mice were treated with broad-spectrum abx leading to GMB perturbation.

The impact of underrepresented minority or marginalized identity status on training outcomes of MD-PhD students.

Dual-degree MD-PhD programs have historically lacked diversity of race, ethnicity, gender, sexual orientation, and other facets of identity. Like MD- and PhD-granting programs, MD-PhD program training environments are also marked by structural barriers that negatively impact measurable academic outcomes of underrepresented and/or marginalized students in academic medicine (racial and ethnic minority groups considered underrepresented by the National Institute of Health, sexual and gender minorities, individuals with disabilities, and individuals of low socioeconomic status). In this article, we review the existing literature on MD-PhD program disparities affecting students from these groups and provide recommendations grounded on the reviewed evidence.

The gut microbiome in Alzheimer's disease: what we know and what remains to be explored.

Alzheimer's disease (AD), the most common cause of dementia, results in a sustained decline in cognition. There are currently few effective disease modifying therapies for AD, but insights into the mechanisms that mediate the onset and progression of disease may lead to new, effective therapeutic strategies. Amyloid beta oligomers and plaques, tau aggregates, and neuroinflammation play a critical role in neurodegeneration and impact clinical AD progression.

Farnesyltransferase inhibitor LNK-754 attenuates axonal dystrophy and reduces amyloid pathology in mice.

Background: Amyloid plaque deposition and axonal degeneration are early events in AD pathogenesis. Aβ disrupts microtubules in presynaptic dystrophic neurites, resulting in the accumulation of impaired endolysosomal and autophagic organelles transporting β-site amyloid precursor protein cleaving enzyme (BACE1). Consequently, dystrophic neurites generate Aβ42 and significantly contribute to plaque deposition.

Poloxamer-188 Exacerbates Brain Amyloidosis, Presynaptic Dystrophies, and Pathogenic Microglial Activation in 5XFAD Mice.

Background: Alzheimer's disease (AD) is initiated by aberrant accumulation of amyloid beta (Aβ) protein in the brain parenchyma. The microenvironment surrounding amyloid plaques is characterized by the swelling of presynaptic terminals (dystrophic neurites) associated with lysosomal dysfunction, microtubule disruption, and impaired axonal transport. Aβ-induced plasma membrane damage and calcium influx could be potential mechanisms underlying dystrophic neurite formation.

Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain.

Background: Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson's disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers.

14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model.

Alpha-synuclein (αsyn) is the key component of proteinaceous aggregates termed Lewy Bodies that pathologically define a group of disorders known as synucleinopathies, including Parkinson's Disease (PD) and Dementia with Lewy Bodies. αSyn is hypothesized to misfold and spread throughout the brain in a prion-like fashion. Transmission of αsyn necessitates the release of misfolded αsyn from one cell and the uptake of that αsyn by another, in which it can template the misfolding of endogenous αsyn upon cell internalization.

Sensitivity and specificity of phospho-Ser129 α-synuclein monoclonal antibodies.

α-Synuclein (α-syn) is an abundant presynaptic protein that is the primary constituent of inclusions that define Lewy body diseases (LBDs). In these inclusions, α-syn is phosphorylated at the serine-129 residue. Antibodies directed to this phosphorylation site are used to measure inclusion abundance and stage disease progression in preclinical models as well as in postmortem tissues in LBDs.

α-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration.

Genetic variation in a major histocompatibility complex II (MHCII)-encoding gene (HLA-DR) increases risk for Parkinson disease (PD), and the accumulation of MHCII-expressing immune cells in the brain correlates with α-synuclein inclusions. However, the timing of MHCII-cell recruitment with respect to ongoing neurodegeneration, and the types of cells that express MHCII in the PD brain, has been difficult to understand. Recent studies show that the injection of short α-synuclein fibrils into the rat substantia nigra pars compacta (SNpc) induces progressive inclusion formation in SNpc neurons that eventually spread to spiny projection neurons in the striatum.