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Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer's disease.

Stranahan AM, Mattson MP - Neural Plast. (2010)

Bottom Line: This paper will cover several hypotheses that attempt to account for age-related alterations among this cell population.We consider whether specific developmental, anatomical, or biochemical features of neurons in layer II of the entorhinal cortex contribute to their particular sensitivity to aging and AD.Taken together, the existing data point to a regional cascade in which entorhinal cortical alterations directly contribute to downstream changes in its primary afferent region, the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychological and Brain Sciences, Johns Hopkins University, Ames Hall, 3400 N. Charles St., Baltimore, MD 21218, USA. alexis.stranahan@jhu.edu

ABSTRACT
All neurons are not created equal. Certain cell populations in specific brain regions are more susceptible to age-related changes that initiate regional and system-level dysfunction. In this respect, neurons in layer II of the entorhinal cortex are selectively vulnerable in aging and Alzheimer's disease (AD). This paper will cover several hypotheses that attempt to account for age-related alterations among this cell population. We consider whether specific developmental, anatomical, or biochemical features of neurons in layer II of the entorhinal cortex contribute to their particular sensitivity to aging and AD. The entorhinal cortex is a functionally heterogeneous environment, and we will also review data suggesting that, within the entorhinal cortex, there is subregional specificity for molecular alterations that may initiate cognitive decline. Taken together, the existing data point to a regional cascade in which entorhinal cortical alterations directly contribute to downstream changes in its primary afferent region, the hippocampus.

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Related in: MedlinePlus

Microenvironmental changes interact with intrinsic cellular alterations to promote the selective vulnerability of entorhinal layer II neurons in aging and AD. Neurons located further away from plaques are likely to maintain a greater degree of structural and functional integrity in AD, while neurons situated close to plaques and in the vicinity of the vasculature are exposed to elevated levels of inflammatory cytokines such as tumor-necrosis factor-alpha (TNF alpha) and monocyte chemoattractant protein 1 (MCP1). Proinflammatory alterations in the local microenvironment, together with intrinsic changes in neuronal reelin (Reln), brain-derived neurotrophic factor (BDNF), and tissue inhibitor of metalloproteinase 3 (TIMP3) expression, could potentially impair synaptic function. This impairment would alter signal propagation both locally, through reductions in NMDA NR1 subunit and muscarinic acetylcholine receptor M1 (mAChR1) expression, and downstream in the hippocampus, through reductions in synaptophysin expression in the terminal fields for layer II entorhinal neurons.
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fig2: Microenvironmental changes interact with intrinsic cellular alterations to promote the selective vulnerability of entorhinal layer II neurons in aging and AD. Neurons located further away from plaques are likely to maintain a greater degree of structural and functional integrity in AD, while neurons situated close to plaques and in the vicinity of the vasculature are exposed to elevated levels of inflammatory cytokines such as tumor-necrosis factor-alpha (TNF alpha) and monocyte chemoattractant protein 1 (MCP1). Proinflammatory alterations in the local microenvironment, together with intrinsic changes in neuronal reelin (Reln), brain-derived neurotrophic factor (BDNF), and tissue inhibitor of metalloproteinase 3 (TIMP3) expression, could potentially impair synaptic function. This impairment would alter signal propagation both locally, through reductions in NMDA NR1 subunit and muscarinic acetylcholine receptor M1 (mAChR1) expression, and downstream in the hippocampus, through reductions in synaptophysin expression in the terminal fields for layer II entorhinal neurons.

Mentions: Layer II neurons show a variety of molecular alterations in AD, including reductions in muscarinic acetylcholine receptor 1, GABAA receptor delta, and ionotropic glutamate receptor NMDA 1 (Figure 2; [35]. These changes occur in layer II neurons that do not exhibit histopathological tangles. In contrast, tangle-bearing neurons in layer II of the AD entorhinal cortex show increased expression of apolipoprotein-J and tissue inhibitor of metalloproteinase-3, relative to non-tanglebearing neurons [36]. The question of whether these molecular changes map onto the different morphological cell types that reside in layer II of the entorhinal cortex remains to be addressed. Additionally, tangle formation occurs earlier in the “transentorhinal region” [13], relative to the entorhinal cortex per se, and the molecular signatures that distinguish different areas within the entorhinal cortex have not yet been identified. Lastly, neurons located close to plaques show a variety of morphological and molecular alterations not observed in neurons located further away from plaques [37], but transcriptional alterations in plaque-neighboring neurons have not yet been characterized.


Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer's disease.

Stranahan AM, Mattson MP - Neural Plast. (2010)

Microenvironmental changes interact with intrinsic cellular alterations to promote the selective vulnerability of entorhinal layer II neurons in aging and AD. Neurons located further away from plaques are likely to maintain a greater degree of structural and functional integrity in AD, while neurons situated close to plaques and in the vicinity of the vasculature are exposed to elevated levels of inflammatory cytokines such as tumor-necrosis factor-alpha (TNF alpha) and monocyte chemoattractant protein 1 (MCP1). Proinflammatory alterations in the local microenvironment, together with intrinsic changes in neuronal reelin (Reln), brain-derived neurotrophic factor (BDNF), and tissue inhibitor of metalloproteinase 3 (TIMP3) expression, could potentially impair synaptic function. This impairment would alter signal propagation both locally, through reductions in NMDA NR1 subunit and muscarinic acetylcholine receptor M1 (mAChR1) expression, and downstream in the hippocampus, through reductions in synaptophysin expression in the terminal fields for layer II entorhinal neurons.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3039218&req=5

fig2: Microenvironmental changes interact with intrinsic cellular alterations to promote the selective vulnerability of entorhinal layer II neurons in aging and AD. Neurons located further away from plaques are likely to maintain a greater degree of structural and functional integrity in AD, while neurons situated close to plaques and in the vicinity of the vasculature are exposed to elevated levels of inflammatory cytokines such as tumor-necrosis factor-alpha (TNF alpha) and monocyte chemoattractant protein 1 (MCP1). Proinflammatory alterations in the local microenvironment, together with intrinsic changes in neuronal reelin (Reln), brain-derived neurotrophic factor (BDNF), and tissue inhibitor of metalloproteinase 3 (TIMP3) expression, could potentially impair synaptic function. This impairment would alter signal propagation both locally, through reductions in NMDA NR1 subunit and muscarinic acetylcholine receptor M1 (mAChR1) expression, and downstream in the hippocampus, through reductions in synaptophysin expression in the terminal fields for layer II entorhinal neurons.
Mentions: Layer II neurons show a variety of molecular alterations in AD, including reductions in muscarinic acetylcholine receptor 1, GABAA receptor delta, and ionotropic glutamate receptor NMDA 1 (Figure 2; [35]. These changes occur in layer II neurons that do not exhibit histopathological tangles. In contrast, tangle-bearing neurons in layer II of the AD entorhinal cortex show increased expression of apolipoprotein-J and tissue inhibitor of metalloproteinase-3, relative to non-tanglebearing neurons [36]. The question of whether these molecular changes map onto the different morphological cell types that reside in layer II of the entorhinal cortex remains to be addressed. Additionally, tangle formation occurs earlier in the “transentorhinal region” [13], relative to the entorhinal cortex per se, and the molecular signatures that distinguish different areas within the entorhinal cortex have not yet been identified. Lastly, neurons located close to plaques show a variety of morphological and molecular alterations not observed in neurons located further away from plaques [37], but transcriptional alterations in plaque-neighboring neurons have not yet been characterized.

Bottom Line: This paper will cover several hypotheses that attempt to account for age-related alterations among this cell population.We consider whether specific developmental, anatomical, or biochemical features of neurons in layer II of the entorhinal cortex contribute to their particular sensitivity to aging and AD.Taken together, the existing data point to a regional cascade in which entorhinal cortical alterations directly contribute to downstream changes in its primary afferent region, the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychological and Brain Sciences, Johns Hopkins University, Ames Hall, 3400 N. Charles St., Baltimore, MD 21218, USA. alexis.stranahan@jhu.edu

ABSTRACT
All neurons are not created equal. Certain cell populations in specific brain regions are more susceptible to age-related changes that initiate regional and system-level dysfunction. In this respect, neurons in layer II of the entorhinal cortex are selectively vulnerable in aging and Alzheimer's disease (AD). This paper will cover several hypotheses that attempt to account for age-related alterations among this cell population. We consider whether specific developmental, anatomical, or biochemical features of neurons in layer II of the entorhinal cortex contribute to their particular sensitivity to aging and AD. The entorhinal cortex is a functionally heterogeneous environment, and we will also review data suggesting that, within the entorhinal cortex, there is subregional specificity for molecular alterations that may initiate cognitive decline. Taken together, the existing data point to a regional cascade in which entorhinal cortical alterations directly contribute to downstream changes in its primary afferent region, the hippocampus.

Show MeSH
Related in: MedlinePlus