Chronic Intermittent Hypoxia Enhances Pathological Tau Seeding, Propagation, and Accumulation and Exacerbates Alzheimer-like Memory and Synaptic Plasticity Deficits and Molecular Signatures.

BACKGROUND: Obstructive sleep apnea, characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), is a risk factor for Alzheimer's disease (AD) progression. Recent epidemiological studies point to CIH as the best predictor of developing cognitive decline and AD in older adults with obstructive sleep apnea. However, the precise underlying mechanisms remain unknown. This study was undertaken to evaluate the effect of CIH on pathological human tau seeding, propagation, and accumulation; cognition; synaptic plasticity; neuronal network excitability; and gene expression profiles in a P301S human mutant tau mouse model of AD and related tauopathies. METHODS: We exposed 4- to 4.5-month-old male P301S and wild-type mice to an 8-week CIH protocol (6-min cycle: 21% O2 to 8% O2 to 21% O2, 80 cycles per 8 hours during daytime) and assessed its effect on tau pathology and various AD-related phenotypic and molecular signatures. Age- and sex-matched P301S and wild-type mice were reared in normoxia (21% O2) as experimental controls. RESULTS: CIH significantly enhanced pathological human tau seeding and spread across connected brain circuitry in P301S mice; it also increased phosphorylated tau load. CIH also exacerbated memory and synaptic plasticity deficits in P301S mice. However, CIH had no effect on seizure susceptibility and network hyperexcitability in these mice. Finally, CIH exacerbated AD-related pathogenic molecular signaling in P301S mice. CONCLUSIONS: CIH-induced increase in pathologic human tau seeding and spread and exacerbation of other AD-related impairments provide new insights into the role of CIH and obstructive sleep apnea in AD pathogenesis.

Neuronal Network Excitability in Alzheimer's Disease: The Puzzle of Similar versus Divergent Roles of Amyloid ß and Tau.

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder that commonly causes dementia in the elderly. Recent evidence indicates that network abnormalities, including hypersynchrony, altered oscillatory rhythmic activity, interneuron dysfunction, and synaptic depression, may be key mediators of cognitive decline in AD. In this review, we discuss characteristics of neuronal network excitability in AD, and the role of Aß and tau in the induction of network hyperexcitability. Many patients harboring genetic mutations that lead to increased Aß production suffer from seizures and epilepsy before the development of plaques. Similarly, pathologic accumulation of hyperphosphorylated tau has been associated with hyperexcitability in the hippocampus. We present common and divergent roles of tau and Aß on neuronal hyperexcitability in AD, and hypotheses that could serve as a template for future experiments.

Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures.

The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer's disease (AD) patients' brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.

Correction: Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer's disease.

The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahiro Okamoto" in the HTML and PDF of the article.

Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer's disease.

Alzheimer's disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole's effect on amyloid beta (Aß) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid ß precursor protein (APP) and presenilin mutations and exhibit early Aß accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced Aß42, Aß40, Aß oligomers levels, and Aß plaque load in 5XFAD mice. RNA-Sequencing showed that riluzole reversed many gene expression changes observed in the hippocampus of 5XFAD mice, predominantly in expression of canonical gene markers for microglia, specifically disease-associated microglia (DAM), as well as neurons and astrocytes. Central to the cognitive improvements observed, riluzole reversed alterations in NMDA receptor subunits gene expression, which are essential for learning and memory. These data demonstrate that riluzole exerts a disease modifying effect in an Aß mouse model of early-onset familial AD.