Malignant Synaptic Growth and Alzheimer‘s Disease

Newman, Ehren L.; Shay, Christopher F.; Hasselmo, Michael E.

doi:10.2217/fnl.12.47

Cited by 6 publications

(7 citation statements)

References 86 publications

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“…Previous models suggested that lower levels of ACh resulting in reduced presynaptic inhibition by muscarinic receptors could lead to excessive synaptic modification that could contribute to the progression of AD (Hasselmo, 1994 ), which is consistent with data showing hyperactivity in the hippocampal formation in presymptomatic AD (Quiroz et al, 2010 ). This framework supports the use of M4 muscarinic agonists to boost presynaptic inhibition and potentially reduce the hyperactivation in AD (Newman et al, 2012 ). Understanding the physiological function of the septo-hippocampal cholinergic system thus remains an important step in basic research.…”

Section: Cholinergic Dysfunction In Alzheimer’s Diseasesupporting

confidence: 69%

Modulation of Hippocampal Circuits by Muscarinic and Nicotinic Receptors

Dannenberg

Young

Hasselmo

2017

Front. Neural Circuits

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This article provides a review of the effects of activation of muscarinic and nicotinic receptors on the physiological properties of circuits in the hippocampal formation. Previous articles have described detailed computational hypotheses about the role of cholinergic neuromodulation in enhancing the dynamics for encoding in cortical structures and the role of reduced cholinergic modulation in allowing consolidation of previously encoded information. This article will focus on addressing the broad scope of different modulatory effects observed within hippocampal circuits, highlighting the heterogeneity of cholinergic modulation in terms of the physiological effects of activation of muscarinic and nicotinic receptors and the heterogeneity of effects on different subclasses of neurons.

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Section: Cholinergic Dysfunction In Alzheimer’s Diseasesupporting

confidence: 69%

Modulation of Hippocampal Circuits by Muscarinic and Nicotinic Receptors

Dannenberg

Young

Hasselmo

2017

Front. Neural Circuits

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“…Notably, neuritic dystrophy can occur early or predominantly at the presynaptic sites without concurrently involving the axonal tract regions, at least in some cases [10, 36-38, 66]. This may be consistent with the notion that neuritic dystrophy may occur as a part of regenerative cellular attempts [53-57, 131, 132]. Thus, extensive investigations are warranted to identify the molecular substrates and signaling pathways responsible for axonal dystrophy, which may lead to the discovery of novel pharmaceutical targets for this pathology.…”

Section: Introductionmentioning

confidence: 52%

Can BACE1 Inhibition Mitigate Early Axonal Pathology in Neurological Diseases?

Xiao

Gai

et al. 2013

JAD

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β-Secretase-1 (BACE1) is the rate-limiting enzyme for the genesis of amyloid-β (Aβ) peptides, the main constituents of the amyloid plaques in the brains of Alzheimer’s disease (AD) patients. BACE1 is being evaluated as an anti-Aβ target for AD therapy. Recent studies indicate that BACE1 elevation is associated with axonal and presynaptic pathology during plaque development. Evidence also points to a biological role for BACE1 in axonal outgrowth and synapse formation during development. Axonal, including presynaptic, pathology exists in AD as well as many other neurological disorders such as Parkinson’s disease, epilepsy, stroke, and trauma. In this review, we discuss pharmaceutical BACE1 inhibition as a therapeutic option for axonal pathogenesis, in addition to amyloid pathology. We first introduce the amyloidogenic processing of amyloid-β protein precursor and describe the normal expression pattern of the amyloidogenic proteins in the brain, with an emphasis on BACE1. We then address BACE1 elevation relative to amyloid plaque development, followed by updating recent understanding of a neurotrophic role of BACE1 in axon and synapse development. We further elaborate the occurrence of axonal pathology in some other neurological conditions. Finally, we propose pharmacological inhibition of excessive BACE1 activity as an option to mitigate early axonal pathology occurring in AD and other neurological disorders.

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“…Firstly, if the same neural circuits simultaneously process external and internal information, then it is difficult for those circuits to separate what is in the environment from what is generated based on priors, memories, and expectations. When newly encoded information is ubiquitously bound to retrieved memories it becomes difficult to distinguish related memories (Hasselmo & Bower, 1993 ), and reencoding of recently retrieved information can result in runaway synaptic strengthening (Newman, Shay, & Hasselmo, 2012b ). Secondly, switching is an important ingredient in algorithms that converge toward accurate high-dimensional internal models (Bengio et al, 2015 ; Heeger, 2017 ; O’Reilly, 1996 ).…”

Section: Clarifications Predictions and Open Questionsmentioning

confidence: 99%

Switching between internal and external modes: A multiscale learning principle

Honey

Newman

Schapiro

2017

Network Neuroscience

102

111

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Brains construct internal models that support perception, prediction, and action in the external world. Individual circuits within a brain also learn internal models of the local world of input they receive, in order to facilitate efficient and robust representation. How are these internal models learned? We propose that learning is facilitated by continual switching between internally biased and externally biased modes of processing. We review computational evidence that this mode-switching can produce an error signal to drive learning. We then consider empirical evidence for the instantiation of mode-switching in diverse neural systems, ranging from subsecond fluctuations in the hippocampus to wake-sleep alternations across the whole brain. We hypothesize that these internal/external switching processes, which occur at multiple scales, can drive learning at each scale. This framework predicts that (a) slower mode-switching should be associated with learning of more temporally extended input features and (b) disruption of switching should impair the integration of new information with prior information.

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Malignant Synaptic Growth and Alzheimer‘s Disease

Cited by 6 publications

References 86 publications

Modulation of Hippocampal Circuits by Muscarinic and Nicotinic Receptors

Modulation of Hippocampal Circuits by Muscarinic and Nicotinic Receptors

Can BACE1 Inhibition Mitigate Early Axonal Pathology in Neurological Diseases?

Switching between internal and external modes: A multiscale learning principle

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