Effects of early adulthood chronic sleep disruption on late life cognition, brain pathology, and microglial reactivity in the PS19 mouse model of tauopathy

Lack of effect of repetitive mild traumatic brain injury early in life on the neuropathological and behavioral hallmarks of Alzheimer's disease in 3xTg-AD mice

Background Repetitive traumatic brain injuries (rTBIs) are predicted to increase risk for neurodegenerative disorders including Alzheimer's disease (AD). Objective By using a combination of behavioral tests and histopathology, we investigated whether brain trauma worsens cognitive dysfunction and brain pathology in 3xTg-AD mice subjected early in life to repetitive mild TBI (rmTBI). Methods At 3 months old, mice in the rmTBI group were given 5 mTBIs, each separated by 48 h. Mice were aged to 10 months old and assessed for cognitive function using the Barnes maze and Novel Object Recognition behavioral tests. Hippocampal sections were stained for amyloid-β and phosphorylated-tau proteins that constitute pathological hallmarks of AD. Immunostaining for GFAP and Iba1 was also employed to assess glial reactivity in the hippocampus. Results Results from the behavioral tests indicate that there are no significant differences in the severity of cognitive dysfunction between any of the 3xTg-AD mouse groups (naïve, SHAM, or rmTBI). As expected, wild-type mice perform better across all behavioral tests than any of the 3xTg-AD mice. Furthermore, we do not find any significant difference in the amount of amyloid-β aggregation, tau phosphorylation, or gliosis between rmTBI and control (naïve or SHAM) 3xTg-AD mouse groups. Conclusions Collectively, our data show that rmTBIs early in life do not accelerate progression or enhance the magnitude of disease in mice that are genetically predisposed to developing AD. These findings suggest that the young brain is quite resilient to trauma and that an enhanced risk of neurodegeneration is not an inescapable conclusion of a history of rmTBI.

From adolescence to Alzheimer’s: a neurodevelopmental lifespan model of cognitive vulnerability

Temporal progression of auditory brainstem dysfunction and behavioral phenotypes in mouse models of tauopathy.

Cognitive decline in Alzheimer's disease and related dementias (AD/ADRD) frequently co-occurs with motor and sensory processing impairments. While auditory abnormalities were reported in beta-amyloid-based models before cognitive decline, the effects of tau pathology on auditory circuit function remain poorly understood. The PS19 mouse model expressing the P301S tau mutation exhibits tau pathology associated with frontotemporal dementia. When combined with the humanized ApoE ɛ4 allele, these mice show accelerated tau accumulation and neurodegeneration. We investigated the temporal progression of auditory and behavioral deficits in PS19 and ApoE4/PS19 mice of either sex at 3 and 7 months. Auditory processing was assessed using auditory brainstem response (ABR) recordings, while anxiety-like and motor behaviors were evaluated using the elevated plus maze (EPM) and rotarod assays. PS19 mice exhibited auditory pathway dysfunction at 3 months, characterized by reduced and delayed neural responses to acoustic stimuli. These auditory deficits occurred without detectable behavioral changes in anxiety- or motor-related measures. By 7 months, cochlear-nucleus-derived ABR activity shifted from an initial reduction to elevation relative to controls, suggesting compensatory hyperexcitability. In contrast, ApoE4/PS19 mice showed reduced ABR amplitudes and shortened response latencies that persisted with age, accompanied by altered anxiety-like behavior and motor performance. Together, these results demonstrate that auditory pathway dysfunction may represent an early marker of tau pathology preceding behavioral impairment. The divergent temporal patterns of ABR alterations across genotypes suggest that genetic context, particularly ApoE4, modulates the progression of tau-driven circuit dysfunction, highlighting ABR as a potential noninvasive biomarker for early tau-related neurodegenerative disease.Significance Statement Early detection of Alzheimer's disease and related dementias remains a major clinical challenge. This study identifies auditory pathway dysfunction as an early, measurable marker of tau pathology, preceding detectable behavioral impairments in mouse models with abnormal auditory brainstem responses (ABRs) appeared months before anxiety or motor behavioral changes. Genetic background also significantly influenced disease progression, with the ApoE4 allele altering both the timing and nature of auditory and behavioral phenotypes. Together, these findings demonstrate that tau pathology disrupts auditory processing at early disease stages and suggest that ABR-based measures as sensitive, non-invasive approach for early detection and monitoring of tau-related neurodegeneration.

Association Between Alzheimer Pathology, Sleep, and Cognition in Patients With Late-Onset Unexplained Epilepsy.

BACKGROUND AND OBJECTIVES Late-onset unexplained epilepsy (LOUE) has been linked to accelerated cognitive decline. However, the role of neurodegenerative proteins and whether they exert their effects through sleep-related mechanisms remain unexplored in this population. The goal of this study was to investigate the association of plasma p-tau217, a measure of Alzheimer disease (AD) pathology, with cognition in LOUE and its association with sleep. METHODS Participants with LOUE, with new-onset unprovoked seizures, age at onset 55 years or older, and absence of cortical lesions on MRI, were prospectively recruited. They underwent cognitive testing which included the extended Preclinical Alzheimer Cognitive Composite (PACC5). A 24-hour EEG was obtained, and sleep manually scored. Measures of sleep macroarchitecture and N2/N3 microarchitecture were extracted including slow oscillation (SO), fast spindle (FS), slow spindle (SS), and spindle-SO coupling measures. RESULTS Eighty-five participants enrolled (mean age 71.3 ± 7.1 years; 49% female). The average PACC5 Z score (±SD) was -0.63 ± 1.0. Higher plasma levels of log-transformed p-tau217 (per 1 unit increase) were associated with poorer cognition, PACC5 (β = -0.66; 95% CI -1.19 to -0.13; p = 0.0017), after adjusting for age, sex, and education. The severity of epilepsy modulated this relationship: individuals with both elevated p-tau217 and medication-refractory epilepsy exhibited worse cognitive performance (refractory epilepsy * p-tau217 interaction term β = -1.49; 95% CI -2.94 to -0.05; p = 0.04). Higher plasma p-tau217 levels were associated with reduced spindle-SO coupling. Mediation analysis indicated that approximately 24% of the association between p-tau217 and cognition was accounted for by spindle-SO coupling (95% CI 3%-85%, p = 0.032). DISCUSSION In individuals with LOUE, elevated plasma p-tau217 was associated with both cognitive impairment and disrupted sleep microarchitecture, with the most pronounced cognitive deficits observed in individuals with medication refractory epilepsy. These findings support the utility of plasma p-tau217 as a biomarker in this population and underscore the role of sleep processes in the relationship between neurodegenerative pathology and cognition in older adults with epilepsy.

Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease

Alzheimer’s disease (AD), though defined as a cognitive disorder, often presents neuropsychiatric symptoms such as anxiety, depression, agitation and sleep disruptions years before the onset of frank memory impairment. An early pathological feature is the accumulation of hyperphosphorylated “pretangle” tau (pTau) in the locus coeruleus (LC), the brain’s primary source of norepinephrine (NE). While clinical studies link LC pTau burden to behavioral abnormalities, causal mechanisms remain unclear. We developed a translationally-relevant mouse model that recapitulates the ‘LC-first’ phenomenon using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation induced anxiety-and compulsive-like behaviors and reduced sleep spindles without altering overall sleep architecture. Consistent with the behavioral phenotypes, electrophysiological recordings revealed significant increases in spontaneous and evoked firing of LC neurons, accompanied by robust astrocytic reactivity with no apparent cell death. Transcriptomic analysis identified upregulation of Hcn2 and downregulation of Clic6, suggesting changes in neuronal excitability. To further define molecular mechanisms, we developed a cell type-specific proteomics approach, which showed synaptic and metabolic alterations associated with LC-specific tau pathology. Early anxiety-like behaviors observed at 3 months diminished at later timepoints (6-9 months) and were replaced by anxiolytic characteristics. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, laying the foundation for the development of LC-based disease-modifying therapies to address neuropsychiatric manifestations.

Instrumental, Neurophysiological, cognitive and Sleep InvestiGations into the High risk of neurodegeneraTion in Late Onset Epilepsy of Unknown aetiology: the INSIGHT-LOEU study.

This strategy could improve the early detection of cognitive decline, guide personalised management, and ultimately enhance quality of life, while contributing to the long-term sustainability of healthcare systems in an ageing population, focusing on LOEU as a model for dementia prevention.