Abstract:Elevated excitability in the hippocampus has emerged as a key contributor to reduced memory function in aging and in cognitive impairment prodromal to Alzheimer’s disease. Here, we investigated the relationship between neural activity and memory in the hippocampus and a connectional cortical network using an aged rat model of individual differences for memory impairment. The expression of cFos was used as a measure of pharmacologically induced neural activity. Aged memory-impaired rats exhibited elevated cFos … Show more
“…This finding was replicated in a recent study using a pharmacological stimulus to induce neuronal activation and detection of activity by expression of the immediate early gene, cFos (Fig. 2A) [22]. cFos was increased in aged memory-impaired rats relative to both young and aged unimpaired rats, exhibiting a tight correlation with memory status such that greater cFos expression in CA3 coincided with poorer memory among the animals in the aged cohort.Fig.…”
Section: Hyperactivity In the Hippocampal Memory System Is Localized supporting
Sporadic late-onset Alzheimer’s disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-017-0541-z) contains supplementary material, which is available to authorized users.
“…This finding was replicated in a recent study using a pharmacological stimulus to induce neuronal activation and detection of activity by expression of the immediate early gene, cFos (Fig. 2A) [22]. cFos was increased in aged memory-impaired rats relative to both young and aged unimpaired rats, exhibiting a tight correlation with memory status such that greater cFos expression in CA3 coincided with poorer memory among the animals in the aged cohort.Fig.…”
Section: Hyperactivity In the Hippocampal Memory System Is Localized supporting
Sporadic late-onset Alzheimer’s disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-017-0541-z) contains supplementary material, which is available to authorized users.
“…In addition, τ-PET signal seems to be detectable in multiple brain regions across functional networks simultaneously rather than in a step-wise manner, which is more supportive of selectively vulnerable brain systems being the etiology as opposed to seed-based templating, although, both mechanisms may occur simultaneously (Walsh and Selkoe, 2016). In this context, it should be noted that functionally connected brain systems, centered in the parietal and posterior cingulate regions, have been found to be abnormal in mouse models of age-related memory impairment, and that this functional stress is alleviated with therapies targeting brain circuits (Haberman et al, 2017). …”
Functionally related brain regions are selectively vulnerable to Alzheimer’s disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer’s disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivo molecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer’s disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer’s disease dementia, we found several distinct spatial patterns of tau deposition, including ‘Braak-like’ and ‘non-Braak-like’, across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with ‘non-Braak-like’ patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer’s disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer’s disease.
“…Substantial previous work has shown that physiological characteristics of CA3 can distinguish between aged rats with impaired or unimpaired memory. Aged impaired rats have elevated CA3 activation, which leads to inability to remap CA3 place cells in novel contexts (Haberman et al, 2017;Wilson et al, 2005). They furthermore have reduced expression of genes related to synaptic plasticity in CA3 (Adams et al, 2001;Haberman et al, 2011Haberman et al, , 2013Smith et al, 2000).…”
Alzheimer's disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment.Hippocampal sharp-wave ripples (SWRs) -electrophysiological signatures of memory reactivation in the hippocampus -are a compelling candidate for doing so. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knock in (apoE4-KI) mice -a model of the major genetic risk factor for AD -we found that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1-2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD.
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