Isolating Pathogenic Mechanisms Embedded within the Hippocampal Circuit through Regional Vulnerability

Small, Scott A.

doi:10.1016/j.neuron.2014.08.030

Cited by 46 publications

(30 citation statements)

References 85 publications

(102 reference statements)

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“…However, the CA3 remains relatively unaffected by comparison (Small et al 2011). Relevant to the present study, there is tentative evidence (both in animal models and postmortem studies in human patients), for dentate gyrus-specific resistance to AD-related changes (Small 2014), though more work is required to substantiate this further.…”

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confidence: 56%

Is riluzole a new drug for Alzheimer's disease?

Whitcomb

Molnár

2015

Journal of Neurochemistry

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Read the full article 'Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression' on page 381.Both experimental and clinical studies indicate that impaired excitatory synaptic transmission, which ultimately culminates in hypoactivity, is a hallmark feature of Alzheimer's disease (AD) pathology. Intriguingly, studies also find that AD patients have a propensity for epileptic seizures, and various in vitro cellular models of AD pathology display hyperactive and dyssynchronous network function (Palop and Mucke 2010). Taken together, this suggests the coexistence of hyperand hypoactivity, which perhaps varies by brain region, neuronal subtype and/or stage of disease (Busche and Konnerth 2015). Glutamate is the major excitatory neurotransmitter in the brain, and so its production, secretion, and clearance are all tightly regulated cellular processes. Dysregulation of glutamate could be critical in the expression of aberrant network activity in AD . However, the underlying mechanisms have not yet been established.A key component of AD pathology is a change to the microtubule-associated protein tau. The protein, which canonically functions to stabilize microtubules, becomes hyperphosphorylated in the disease, leading to formation of aggregates termed paired-helical filaments, which are considered neurotoxic. Though first thought of as a predominantly neuronal axon protein, growing evidence now suggests that tau is also present in other subcellular compartments, such as dendritic spines (Kimura et al. 2014), as well as in glial cells. Under pathological conditions tau seems to accumulate in astrocytes (Berry et al. 2001). However, the physiological role for tau in glial cells is yet to be fully characterized.A number of mutations to the tau gene have been identified as risk factors for hereditary tauopathy (Wolfe 2009). One such is the P301L mutation, which has been explored in detail following the generation of a doxycycline-suppressed transgenic mutant mouse (SantaCruz et al. 2005). The exact toxicity of this tau mutation may be due to the reduced binding affinity with microtubules and a propensity for aggregation (Hong et al. 1998). One of the clear advantages of this model is the delayed onset of tauopathy, avoiding potential confounding factors that may arise if pathological tau were to be expressed during development, and perhaps more closely following the late-onset nature of tauopathy in human AD. However, it is important to acknowledge that the P301L model, focusing on tau expression, does not consider any significant contribution from amyloid beta, widely considered to partner hyperphosphorylated tau in driving AD pathogenesis. Thus, as is the case with many transgenic models, findings and interpretations must be caveated.Riluzole [2-amino-6-(trifluoromethoxy) benzothiazole] functions as a sodium channel blocker, and is a US Food and Drug Administration-approved disease-modifying drug for amyotrophic lateral sclerosis. A number of studies have now establ...

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supporting

confidence: 56%

Is riluzole a new drug for Alzheimer's disease?

Whitcomb

Molnár

2015

Journal of Neurochemistry

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“…Recent studies investigating the functions of the hippocampus along its longitudinal axis concluded that the tail is most sensitive to ischemia and that the dentate gyrus is the most likely place where age related cognitive decline could start. [8–10] Possibly the calcifications as seen on CT are related to VFC and reflect these aging related changes. VFC was also found in patients with Alzheimer’s disease.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal Calcification on Computed Tomography in Relation to Cognitive Decline in Memory Clinic Patients: A Case-Control Study

et al. 2016

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BackgroundIt was recently shown that calcification of the hippocampus can be detected on computed tomography (CT) images and these calcifications occur in up to 20% of people over 50 years of age. However, little is known about hippocampal calcification and its relation to cognition and cognitive decline. Therefore, the aim of this study was to (1) determine the prevalence of hippocampal calcification on CT in memory clinic patients controls, and (2) to assess its relation with cognitive decline.Methods67 patients from a memory clinic (cases) were matched by age and gender to a control group. In both groups, hippocampal calcification was assessed by two raters on thin slice, non-contrast enhanced brain CT images. Calcifications were scored bilaterally on presence and severity (absent, mild, moderate, severe). Mini Mental State Exam (MMSE) score was determined in cases.ResultsHippocampal calcification presence was significantly higher in cases (N = 26, 38.8%) compared to controls (N = 9, 13.4%) (P < .01) with an odds ratio of 4.40 (95%CI: 1.63–14.87). In cases, MMSE score was significantly lower in those with hippocampal calcification compared to those without (21.6 vs 24.5, p = .02).ConclusionIn this case-control study we found significantly more hippocampal calcification in patients with cognitive decline as compared to controls. Furthermore, within the cases, MMSE score was significantly lower in those with hippocampal calcification.

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“…One way to isolate pathogenic mechanisms within the hippocampal circuit is to study its regional vulnerability (Small, ). Indeed, the hippocampus is composed of distinct subfields whose morphological, cellular, molecular, functional, and connectivity profiles are very different: the dentate gyrus, the cornu ammonis (CA, with subdivisions from CA1 to CA4) and the subiculum.…”

Section: Introductionmentioning

confidence: 99%