Alzheimer's disease (AD) is characterized by aggregation and deposition of the amyloid-beta (Aβ) protein in patients' brains, with aging contributing through oxidative stress and neuroinflammation. Sleep disturbances are common in patients with AD and exacerbate cognitive impairment. However, it remains unclear how aggregation of specific Aβ species in distinct brain regions contributes to sleep dysfunction. To address this, we characterized amyloid fibrils formed by Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42) by assessing their structural and surface properties using fluorescence, CD, and NMR spectroscopy. Their morphology was also visualized using TEM and AFM. These analyses revealed that Aβ42 aggregates faster than Aβ40 and forms amyloid fibrils with distinct structural, surface, and morphological properties. To investigate their effects in vivo, we bilaterally injected Aβ40 and Aβ42 fibrils into the hippocampus of wild-type mice and recorded the electroencephalogram and electromyogram under freely moving conditions. Aβ42 amyloid fibrils significantly disrupted sleep architecture, particularly REM sleep, and altered oscillations, accompanied by neuronal loss. In contrast, Aβ40 amyloid fibrils mainly affected cortical activity with minimal neuronal loss and caused comparatively modest changes in sleep. These findings demonstrate that a single administration of Aβ amyloid fibril is sufficient to alter sleep/wakefulness state and cortical oscillations. The observed effects differ depending on the type of Aβ administered, suggesting that the physicochemical properties of the fibrils are closely linked to their capacity to induce sleep impairment. These findings shed light on AD-associated sleep disorders, which are differentially affected by the distinct properties of Aβ40 and Aβ42 aggregates.

Liquid-liquid phase separation (LLPS) of proteins implicated in neurodegenerative diseases has gained growing attention in recent years, due to its potential role in driving the transition from functional protein monomers to pathogenic aggregates. However, the mechanisms by which phase separation contributes to the loss of protein function and promotes aggregation remain poorly understood. Recent studies show that multiple proteins or other biomolecules can colocalize within the biomolecular condensates, creating a highly interactive microenvironment that can modulate aggregation. In this review we look into the heterotypic phase separation of tau and α-synuclein, the two key proteins responsible for critical neurodegenerative disorders. By compiling recent findings, this review highlights the modulatory role of heterotypic condensates in disease progression and aims to provide an alternative perspective on regulation of protein aggregation in neurodegeneration.