This Funding Opportunity Announcement (FOA) invites applications that will: (1) promote the development of a comprehensive characterization of brain circuits susceptible to Alzheimer’s disease type pathology and/or neurodegeneration in mouse models of Alzheimer’s disease (AD), (2) share data on the cell connectome in the aging and AD brain in a common reference brain cell atlas that integrates both molecular and anatomical annotations, and (3) complement and extend research on vulnerable cell types to include the mapping of connectivity changes between cells in aging and AD and provide a greater understanding of the mechanisms underlying resilience and vulnerability in AD.
Alzheimer’s disease (AD) is the leading cause of dementia in those over the age of 65, and as many as 5.8 million Americans age 65 and older are living with AD. As the population ages, the number of people age 65 and older with AD is projected to increase between two- and three-fold by 2050. AD is one of the most persistent and devastating dementing disorders of old age because it leads to a complete loss of memory and of the ability to function independently.
A general characteristic of many neurodegenerative diseases, including Alzheimer’s disease, is that the disease impacts specific brain area(s). The pathology worsens with time and impacts more regions in a stereotypical and often predictable fashion. The first step in understanding mechanisms underpinning AD onset and progression is to identify which circuits, and which component(s) of that circuit, are particularly vulnerable. This will allow further development of models that reproduce spatial and temporal features of the pathology, and the identification of intrinsic morphological, electrophysiological, and biochemical properties of vulnerable circuits and novel insights on the types of neurons vulnerable to degeneration.
Despite the fundamental importance of brain connectivity, our knowledge of it remains remarkably incomplete. C. elegans is the only species for which a complete wiring diagram of its 302 neurons has been developed. A mesoscale connectome of the adult mouse is currently being developed. Such a connectome represents a first systematic step towards the full understanding of the complex connectivity in the mammalian brain. Although a mesoscale connectome provides a comprehensive and quantitative database of inter-areal projections, the cell-type-specificity projections remain incomplete. While cell specificity in retrograde tracing can be established, for example with AAV expressing Cre-driver vectors, the nature of target cells in such experiments remains undetermined. However, unprecedented progress in single-cell transcriptomics and epigenomics technologies allows a full characterization of target cells in tracing experiments, thus potentially providing a complete description of the brain connectome at the cellular level. Indeed, proof-of-concept for such an approach is suggested by studies on shared and distinct transcriptomic cell types across neocortical areas.
The systematic identification, characterization, and positional mapping of various cell types and circuits in the adult mouse brain have been recently undertaken by the BRAIN Initiative, in which the National Institute on Aging actively participates. Although research supported by the BRAIN Initiative will reveal fundamental organizational principles of the mammalian nervous system, and provide invaluable resources for neuroscientists in aging research, its focus is not on aging research and neurodegenerative diseases such as Alzheimer’s disease or Alzheimer’s disease related dementias (ADRD).
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