In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies.Copyright © 2021 Elsevier Ltd. All rights reserved.

Neuronal and synaptic loss is characteristic in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer's disease. Recently, we showed that inducing gamma oscillations with visual stimulation (gamma entrainment using sensory stimuli, or GENUS) reduced amyloid plaques and phosphorylated tau in multiple mouse models. Whether GENUS can affect neurodegeneration or cognitive performance remains unknown. Here, we demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, and reducing DNA damage in neurons while also reducing inflammatory response in microglia.Copyright © 2019 Elsevier Inc. All rights reserved.

Microglia, the primary immune cells of the brain, play a key role in pathological and normal brain function. Growing efforts aim to reveal how these cells may be harnessed to treat both neurodegenerative diseases such as Alzheimer's and developmental disorders such as schizophrenia and autism. We recently showed that using noninvasive exposure to 40-Hz white-light (4,000 K) flicker to drive 40-Hz neural activity transforms microglia into an engulfing state and reduces amyloid beta, a peptide thought to initiate neurotoxic events in Alzheimer's disease (AD). This article describes how to construct an LED-based light-flicker apparatus, expose animals to 40-Hz flicker and control conditions, and perform downstream assays to study the effects of these stimuli. Light flicker is simple, faster to implement, and noninvasive, as compared with driving 40-Hz activity using optogenetics; however, it does not target specific cell types, as is achievable with optogenetics. This noninvasive approach to driving 40-Hz neural activity should enable further research into the interactions between neural activity, molecular pathology, and the brain's immune system. Construction of the light-flicker system requires ~1 d and some electronics experience or available guidance. The flicker manipulation and assessment can be completed in a few days, depending on the experimental design.

Gamma rhythms are commonly observed in many brain regions during both waking and sleep states, yet their functions and mechanisms remain a matter of debate. Here we review the cellular and synaptic mechanisms underlying gamma oscillations and outline empirical questions and controversial conceptual issues. Our main points are as follows: First, gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition. Second, gamma oscillations are short-lived and typically emerge from the coordinated interaction of excitation and inhibition, which can be detected as local field potentials. Third, gamma rhythm typically concurs with irregular firing of single neurons, and the network frequency of gamma oscillations varies extensively depending on the underlying mechanism. To document gamma oscillations, efforts should be made to distinguish them from mere increases of gamma-band power and/or increased spiking activity. Fourth, the magnitude of gamma oscillation is modulated by slower rhythms. Such cross-frequency coupling may serve to couple active patches of cortical circuits. Because of their ubiquitous nature and strong correlation with the "operational modes" of local circuits, gamma oscillations continue to provide important clues about neuronal population dynamics in health and disease.

Gamma-band activity (30-90 Hz) and the synchronization of neural activity in the gamma-frequency range have been observed in different cortical and subcortical structures and have been associated with different cognitive functions. However, it is still unknown whether gamma-band synchronization subserves a single universal function or a diversity of functions across the full spectrum of cognitive processes. Here, we address this question reviewing the mechanisms of gamma-band oscillation generation and the functions associated with gamma-band activity across several cortical and subcortical structures. Additionally, we raise a plausible explanation of why gamma rhythms are found so ubiquitously across brain structures. Gamma band activity originates from the interplay between inhibition and excitation. We stress that gamma oscillations, associated with this interplay, originate from basic functional motifs that conferred advantages for low-level system processing and multiple cognitive functions throughout evolution. We illustrate the multifunctionality of gamma-band activity by considering its role in neural systems for perception, selective attention, memory, motivation and behavioral control. We conclude that gamma-band oscillations support multiple cognitive processes, rather than a single one, which, however, can be traced back to a limited set of circuit motifs which are found universally across species and brain structures. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Alzheimer's disease (AD) is characterized by the accumulation of the tau protein in neurons, neurodegeneration and memory loss. However, the role of non-neuronal cells in this chain of events remains unclear. In the present study, we found accumulation of tau in hilar astrocytes of the dentate gyrus of individuals with AD. In mice, the overexpression of 3R tau specifically in hilar astrocytes of the dentate gyrus altered mitochondrial dynamics and function. In turn, these changes led to a reduction of adult neurogenesis, parvalbumin-expressing neurons, inhibitory synapses and hilar gamma oscillations, which were accompanied by impaired spatial memory performances. Together, these results indicate that the loss of tau homeostasis in hilar astrocytes of the dentate gyrus is sufficient to induce AD-like symptoms, through the impairment of the neuronal network. These results are important for our understanding of disease mechanisms and underline the crucial role of astrocytes in hippocampal function.

The complex relationship between specific hippocampal oscillation frequency deficit and cognitive dysfunction in the ischemic brain is unclear. Here, using a mouse two-vessel occlusion (2VO) cerebral ischemia model, we show that visual stimulation with a 40 Hz light flicker drove hippocampal CA1 slow gamma and restored 2VO-induced reduction in CA1 slow gamma power and theta-low gamma phase-amplitude coupling, but not those of the high gamma. Low gamma frequency lights at 30 Hz, 40 Hz, and 50 Hz, but not 10 Hz, 80 Hz, and arrhythmic frequency light, were protective against degenerating CA1 neurons after 2VO, demonstrating the importance of slow gamma in cognitive functions after cerebral ischemia. Mechanistically, 40 Hz light flicker enhanced RGS12-regulated CA3-CA1 presynaptic N-type calcium channel-dependent short-term synaptic plasticity and associated postsynaptic long term potentiation (LTP) after 2VO. These results support a causal relationship between CA1 slow gamma and cognitive dysfunctions in the ischemic brain.

Slow gamma oscillations (30-60 Hz) correlate with retrieval of spatial memory. Altered slow gamma oscillations have been observed in Alzheimer's disease. Here, we use the J20-APP AD mouse model that displays spatial memory loss as well as reduced slow gamma amplitude and phase-amplitude coupling to theta oscillations phase. To restore gamma oscillations in the hippocampus, we used optogenetics to activate medial septal parvalbumin neurons at different frequencies. We show that optogenetic stimulation of parvalbumin neurons at 40 Hz (but not 80 Hz) restores hippocampal slow gamma oscillations amplitude, and phase-amplitude coupling of the J20 AD mouse model. Restoration of slow gamma oscillations during retrieval rescued spatial memory in mice despite significant plaque deposition. These results support the role of slow gamma oscillations in memory and suggest that optogenetic stimulation of medial septal parvalbumin neurons at 40 Hz could provide a novel strategy for treating memory deficits in AD.

We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer's disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function.Copyright © 2019 Elsevier Inc. All rights reserved.

Many neurodegenerative and neurological diseases are rooted in dysfunction of the neuroimmune system; therefore, manipulating this system has strong therapeutic potential. Prior work has shown that exposing mice to flickering lights at 40 Hz drives gamma frequency (∼40 Hz) neural activity and recruits microglia, the primary immune cells of the brain, revealing a novel method to manipulate the neuroimmune system. However, the biochemical signaling mechanisms between 40 Hz neural activity and immune recruitment remain unknown. Here, we exposed wild-type male mice to 5-60 min of 40 Hz or control flicker and assessed cytokine and phosphoprotein networks known to play a role in immune function. We found that 40 Hz flicker leads to increases in the expression of cytokines which promote microglial phagocytic states, such as IL-6 and IL-4, and increased expression of microglial chemokines, such as macrophage-colony-stimulating factor and monokine induced by interferon-γ. Interestingly, cytokine effects differed as a function of stimulation frequency, revealing a range of neuroimmune effects of stimulation. To identify possible mechanisms underlying cytokine expression, we quantified the effect of the flicker on intracellular signaling pathways known to regulate cytokine levels. We found that a 40 Hz flicker upregulates phospho-signaling within the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. While cytokine expression increased after 1 h of 40 Hz flicker stimulation, protein phosphorylation in the NF-κB pathway was upregulated within minutes. Importantly, the cytokine expression profile induced by 40 Hz flicker was different from cytokine changes in response to acute neuroinflammation induced by lipopolysaccharides. These results are the first, to our knowledge, to show how visual stimulation rapidly induces critical neuroimmune signaling in healthy animals. Prior work has shown that exposing mice to lights flickering at 40 Hz induces neural spiking activity at 40 Hz (within the gamma frequency) and recruits microglia, the primary immune cells of the brain. However, the immediate effect of 40 Hz flicker on neuroimmune biochemical signaling was unknown. We found that 40 Hz flicker leads to significant increases in the expression of cytokines, key immune signals known to recruit microglia. Furthermore, we found that 40 Hz flicker rapidly changes the phosphorylation of proteins in the NF-κB and MAPK pathways, both known to regulate cytokine expression. Our findings are the first to delineate a specific rapid immune signaling response following 40 Hz visual stimulation, highlighting both the unique nature and therapeutic potential of this treatment.Copyright © 2020 Garza et al.

It is known that proteins associated with Alzheimer's disease (AD) pathogenesis are significantly reduced by 40 Hz entrainment in mice. If this were to translate to humans, verifying that such a light stimulus can induce a 40 Hz entrainment response in humans and harnessing insights from these case studies could be one step in the development of a multisensory device to prevent and treat AD.Verify the inducement of a 40 Hz response in the human brain by a 40 Hz light stimulus and obtain insights that could potentially aid in the development of a multisensory device for the prevention and treatment of AD.Electroencephalographic brain activity was recorded simultaneously with application of stimulus at different frequencies and intensities. Power spectral densities were analyzed.Entrainment to visual stimuli occurred with the largest response at 40 Hz. The high intensity 40 Hz stimulus caused widespread entrainment. The number of electrodes demonstrating entrainment increased with increasing light intensity. Largest amplitudes for the high intensity 40 Hz stimulus were consistently found at the primary visual cortex. There was a harmonic effect at double the frequency for the 40 Hz stimulus. An eyes-open protocol caused more entrainment than an eyes-closed protocol.It was possible to induce widespread entrainment using a 40 Hz light stimulus in this sample cohort. Insights gleaned from these case studies could potentially aid in the development of a multisensory medical device to prevent and treat AD.

There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-β in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer's disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found that 40-Hz flickering simulation did not engage native gamma oscillations in these regions. Additionally, spike responses in the hippocampus were weak, suggesting 40-Hz light does not effectively entrain deep structures. Mice avoided 40-Hz flickering light, associated with elevated cholinergic activity in the hippocampus. We found no reliable changes in plaque count or microglia morphology by either immunohistochemistry or in vivo two-photon imaging following 40-Hz stimulation, nor reduced levels of amyloid-β 40/42. Thus, visual flicker stimulation may not be a viable mechanism for modulating activity in deep structures.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.