Implication of tau propagation on neurodegeneration in Alzheimer's disease.

Propagation of tau fibrils correlate closely with neurodegeneration and memory deficits seen during the progression of Alzheimer's disease (AD). Although it is not well-established what drives or attenuates tau spreading, new studies on human brain using positron emission tomography (PET) have shed light on how tau phosphorylation, genetic factors, and the initial epicenter of tau accumulation influence tau accumulation and propagation throughout the brain. Here, we review the latest PET studies performed across the entire AD continuum looking at the impact of amyloid load on tau pathology. We also explore the effects of structural, functional, and proximity connectivity on tau spreading in a stereotypical manner in the brain of AD patients. Since tau propagation can be quite heterogenous between individuals, we then consider how the speed and pattern of propagation are influenced by the starting localization of tau accumulation in connected brain regions. We provide an overview of some genetic variants that were shown to accelerate or slow down tau spreading. Finally, we discuss how phosphorylation of certain tau epitopes affect the spreading of tau fibrils. Since tau pathology is an early event in AD pathogenesis and is one of the best predictors of neurodegeneration and memory impairments, understanding the process by which tau spread from one brain region to another could pave the way to novel therapeutic avenues that are efficient during the early stages of the disease, before neurodegeneration induces permanent brain damage and severe memory loss.

Impact of non-neuronal cells in Alzheimer's disease from a single-nucleus profiling perspective.

The role of non-neuronal cells has been relatively overlooked in Alzheimer's disease (AD) neuropathogenesis compared to neuronal cells since the first characterization of the disease. Genome wide-association studies (GWAS) performed in the last few decades have greatly contributed to highlighting the critical impact of non-neuronal cells in AD by uncovering major genetic risk factors that are found largely in these cell types. The recent development of single cell or single nucleus technologies has revolutionized the way we interrogate the transcriptomic and epigenetic profiles of neurons, microglia, astrocytes, oligodendrocytes, pericytes, and endothelial cells simultaneously in the same sample and in an individual manner. Here, we review the latest advances in single-cell/nucleus RNA sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to more accurately understand the function of non-neuronal cells in AD. We conclude by giving an overview of what still needs to be achieved to better appreciate the interconnected roles of each cell type in the context of AD.

Selective Menin Deletion in the Hippocampal CA1 Region Leads to Disruption of Contextual Memory in the MEN1 Conditional Knockout Mouse: Behavioral Restoration and Gain of Function following the Reintroduction of MEN1 Gene.

Cholinergic neuronal networks in the hippocampus play a key role in the regulation of learning and memory in mammals. Perturbations of these networks, in turn, underlie neurodegenerative diseases. However, the mechanisms remain largely undefined. We have recently demonstrated that an in vitro MEN1 gene deletion perturbs nicotinic cholinergic plasticity at the hippocampal glutamatergic synapses. Furthermore, MEN1 neuronal conditional knockout in freely behaving animals has also been shown to result in learning and memory deficits, though the evidence remains equivocal. In this study, using an AVV viral vector transcription approach, we provide direct evidence that MEN1 gene deletion in the CA1 region of the hippocampus indeed leads to contextual fear conditioning deficits in conditional knockout animals. This loss of function was, however, recovered when the same animals were re-injected to overexpress MEN1. This study provides the first direct evidence for the sufficiency and necessity of MEN1 in fear conditioning, and further endorses the role of menin in the regulation of cholinergic synaptic machinery in the hippocampus. These data underscore the importance of further exploring and revisiting the cholinergic hypothesis that underlies neurodegenerative diseases that affect learning and memory.

Spatiotemporal Patterns of Menin Localization in Developing Murine Brain: Co-Expression with the Elements of Cholinergic Synaptic Machinery.

Menin, a product of MEN1 (multiple endocrine neoplasia type 1) gene is an important regulator of tissue development and maintenance; its perturbation results in multiple tumors-primarily of the endocrine tissue. Despite its abundance in the developing central nervous system (CNS), our understanding of menin's role remains limited. Recently, we discovered menin to play an important role in cholinergic synaptogenesis in the CNS, whereas others have shown its involvement in learning, memory, depression and apoptosis. For menin to play these important roles in the CNS, its expression patterns must be corroborated with other components of the synaptic machinery imbedded in the learning and memory centers; this, however, remains to be established. Here, we report on the spatio-temporal expression patterns of menin, which we found to exhibit dynamic distribution in the murine brain from early development, postnatal period to a fully-grown adult mouse brain. We demonstrate here that menin expression is initially widespread in the brain during early embryonic stages, albeit with lower intensity, as determined by immunohistochemistry and gene expression. With the progression of development, however, menin expression became highly localized to learning, memory and cognition centers in the CNS. In addition to menin expression patterns throughout development, we provide the first direct evidence for its co-expression with nicotinic acetylcholine, glutamate and GABA (gamma aminobutyric acid) receptors-concomitant with the expression of both postsynaptic (postsynaptic density protein PSD-95) and presynaptic (synaptotagamin) proteins. This study is thus the first to provide detailed analysis of spatio-temporal patterns of menin expression from initial CNS development to adulthood. When taken together with previously published studies, our data underscore menin's importance in the cholinergic neuronal network assembly underlying learning, memory and cognition.