Alzheimer’s disease is the leading neurological aging disorder impacting the lives of nearly 7 million Americans and 55 million individuals around the world. Alzheimer’s is the most common form of dementia, which is a general term for changes in cognitive abilities that interfere with daily life, such as memory loss. This disease is progressive, starting with mild memory loss, and can lead to the loss of the ability to carry out a conversation (source, Alzheimer’s Association). Although possible in younger individuals, symptoms usually present themselves over the age of 60 (source; CDC), with the risk doubling every 5 years past the age of 65 (source; Alzheimer’s & Dementia).
With the number of individuals living with Alzheimer’s expected to reach nearly 14 million people by 2060, what is being done to study this disease and help those living with it?
Alzheimer’s and dementia research funding at the National Institutes of Health (NIH) is more than $3 billion annually (source, NIH), yet one of the biggest challenges in fully understanding the disease and developing new therapeutics that can catch the disease before symptoms present themselves is the difficulty of conducting in vivo studies. Currently, scientists believe that plaques, deposits of amyloid-beta (Aβ), and tangles, twisted fibers of tau, are the main drivers of irreversible damage and death of nerve cells in the brain (source, Alzheimer’s Association)—changes that can appear years before the disease even presents itself.
Since Alzheimer’s primarily affects older individuals, it’s crucial to find a way to monitor aging in fragile animal models. Inscopix miniscopes provide a novel approach to this challenge by supporting in vivo rodent models with greater translatability to humans. This blog highlights several key publications from researchers using our tools to uncover both the basic and translational science behind Alzheimer’s disease, as well as how the Inscopix Discovery Lab can support these breakthroughs with standardized assays and custom neurobehavioral studies.
Basic Science
Basic science is crucial in Alzheimer’s research, providing insights into the disease’s biological processes and helping identify targets for early intervention and treatment.
Control of contextual memory through interneuronal a5-GABAA receptors
Those with Alzheimer’s struggle with learning and memory, and one research group wanted to investigate how γ-aminobutyric acid type A receptors (GABAARs), typically responsible for mediating inhibitory synaptic transmission in the brain, control contextual memory. It is already known that GABAARs with incorporated α5 subunits (α5-GABAARs) play an important role in learning and memory, with several therapeutic agents targeting these receptors most highly concentrated in the hippocampus. These agents enhance cognition for not only Alzheimer’s disease, but also Down syndrome, autism, and schizophrenia.
Mengwen Zhu and Robert A Pearce’s team of researchers at the University of Wisconsin-Madison used nVoke, affixed to a gradient refractive index (GRIN) lens, for behavioral and calcium imaging experiments aimed at understanding the role that interneuronal α5-GABAARs play in learning suppression, spatial learning, and memory suppression. With these techniques, the group could quantify the place-specific firing of individual neurons, and their new understanding of the important role α5-GABAARs play on interneurons will be a valuable resource for both discovering and developing new targeted therapeutics.
Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model
Tau pathology-induced conditions, or tauopathies, are characterized by brain atrophy and memory impairment due to tau protein hyperphosphorylation and subsequent formation of neurofibrillary tangles (NFTs). Alzheimer’s is a common example of a tauopathy and the subject of several experimental studies that are producing growing evidence that tau oligomers, precursors to NFTs, are more toxic to the brain than the formation of tangles. The research group supported by Lundbeck, wanted to fill a gap in knowledge with research by looking at the role of state-dependent V1PNs activity in young rTg4510 mice prior to neurodegeneration on a single cell level, in vivo.
Using nVista and a ProView™ GRIN lens for single-cell calcium imaging, they investigated cortical visual processing from thousands of defined V1 pyramidal neurons (V1PNs) during visual stimulation and recorded their response to GABAergic tone modulation in young freely moving rTg4510 mice. They also investigated whether electroencephalogram (EEG) oscillations could be used as an early-stage biomarker for tauopathies. Their work provides a detailed functional profile of V1PN impairments in basal/evoked states in a murine tauopathy model, and their single-cell data gives insights into early-stage tauopathy and electroencephalogram (EEG) alterations. These results could help to create a more complete picture of neuronal impairments before neurodegeneration—an overarching goal of many neuroscientists.
Aβ is the primary component of plaques in Alzheimer’s disease (AD), and it is universally suggested by neuroscientists that changes in these deposits cause neural hyperactivity, neuronal firing instability, and homeostasis network collapse in the hippocampus. However, clinical trials with anticonvulsants or neural system suppressors targeting these areas have failed to improve cognitive symptoms in Alzheimer’s. Therefore, a research team with Heng Zhou and Stephen N. Gomperts at Massachusetts General Hospital wanted to determine 1) How Aβ deposits impact hippocampal dynamic calcium activity, and 2) How hippocampal local field potential (LFP) rhythms and coordination across the distinct brain states underly memory encoding and consolidation.
This team used a combination of techniques, including large-scale dynamic calcium imaging with the nVista and concomitant cortical and hippocampal LFP recordings. The imaging was performed in hippocampal CA1 neurons and the LFP recordings were done across the sleep-wake cycle of aged APPswe/PS1dE9 (APP/PS1) transgenic mice. Their findings show that there are multiple distinct effects of Aβ on neural circuit function that vary across behavioral brain states. Keeping this variability in mind can help improve preclinical drug selection for Alzheimer’s.
Translational Science
Translational science connects basic research with clinical application, turning lab discoveries into potential Alzheimer’s treatments and speeding up new interventions and early diagnosis.
Ensemble dynamics of GABAergic interneurons represent memory encoding and retrieval, but a recent study led by Kyerl Park and Jeehyun Kwag at Seoul National University wanted to dive deeper into this topic and explore how GABAergic interneuron dysfunction affects inhibitory ensemble dynamics in Alzheimer’s. The retrosplenial cortex (RSC) contains neurons that have been found to encode contextual fear memory, so this team performed calcium imaging in RSC parvalbumin (PV)-expressing interneurons during a contextual fear memory task in healthy control mice and the 5XFAD mouse model of AD.
The nVoke equipped with a GRIN lens was used for a holistic view of how RSC PV interneurons and ensembles are involved in contextual fear memory encoding. Their methods supported a combination of in vivo and in vitro neural circuit analysis and optogenetic manipulations with several key findings, including memory-encoding PV interneuron ensemble dynamics, which were selectively upregulated during memory retrieval sessions. Their results can help uncover therapeutic targets in Alzheimer’s with insights into the neural circuit mechanisms of memory processing.
The presymptomatic phase of Alzheimer’s occurs 10-20 years before cognitive impairments, but the circuit mechanisms that underlie resilience to its synaptic, circuit, and cognitive dysfunctions in the context of neuropathology remain largely unknown. One existing finding is that aberrations in low-arousal brain states (e.g. general anesthesia or sleep) have been associated with an increased risk of Alzheimer’s pathology, but how general anesthesia can impact the progression of the disease is not yet well understood.
Recent work by Shiri Shob and Inna Slutsky from Tel Aviv University found that general anesthesia exposes dyshomeostasis of CA1 neuronal activity and interictal epileptiform spikes (IESs) during the prodromal, or early phase, disease stage in distinct familial Alzheimer’s Disease (fAD) mouse models. This served as the basis for their more recent study investigating the functional consequences of interictal epileptiform spikes (IESs) and the neuronal circuitry involved in their regulation. nVista was used for time-lapse imaging in behaving mice to determine the responses of hippocampal circuits to anesthesia at the transcriptional, electrophysiological, and behavior levels in fAD mice. This study performed in a mouse model of fAD, has exciting implications for unraveling the circuit mechanisms that contribute to cognitive resilience in Alzheimer’s.
Building on these exciting findings, Inscopix remains committed to advancing our understanding of Alzheimer’s disease through cutting-edge technology and preclinical research. The Inscopix Discovery Lab extends this mission by providing contract research services that utilize our miniscope technology.
Inscopix Discovery Lab
In the Discovery Lab, we’ve partnered with pharmaceutical and biotech companies to address some of the most complex challenges in neuroscience. Our state-of-the-art in vivo rodent R&D facility enables preclinical studies beyond traditional in vitro pharmacology, offering several standardized assays and custom neurobehavioral studies.
A notable example is our collaboration with a leading pharmaceutical partner, where we used our nVue system to investigate amyloid-beta (Aβ) plaque development and neural circuit dynamics in an Alzheimer’s disease mouse model. This allowed us to simultaneously image Ca2+ activity from hundreds of neurons and track Aβ plaques during free behavior, enabling longitudinal assessments of both neural circuit function and plaque progression over time.
This approach is crucial for developing monoclonal antibodies that confirm plaque clearance and restore normal circuit function without side effects. By simultaneously imaging cellular activity and plaque progression over time, we can track circuit phenotypes and identify optimal windows for early therapeutic intervention. These insights enhance our understanding of disease mechanisms and boost the potential for more effective therapies, ultimately improving patient outcomes.
Topics: Miniscope, Calcium Imaging, Memory
Melissa Martin is the Life Science Writer for Bruker Fluorescence Microscopy with a B.S. in Zoology and Life Sciences Communication from the University of Wisconsin-Madison. She is passionate about a wide variety of scientific topics, including brain-neuron behavior and wildlife ecosystem adaptations during climate change. She enjoys conducting interviews and reading about researchers’ work in cell biology, neuroscience, and genomics and hopes to continue to share what she learns with others in an exciting and positive way.