Dataset Information

Amyloid deposition is associated with different patterns of hippocampal connectivity in men versus women.

ABSTRACT: Compared to men, women are disproportionally affected by Alzheimer's disease (AD) and have an accelerated trajectory of cognitive decline and disease progression. Neurobiological factors underlying gender differences in AD remain unclear. This study investigated brain beta-amyloid (A?)-related neural system differences in cognitively normal older men and women (N = 61; 41 females, 65-93 years old). We found that men and women showed different associations between A? load and hippocampal functional connectivity. During associative memory encoding, in men greater A? burden was accompanied by greater hippocampus-prefrontal connectivity (i.e., more synchronized activities), whereas in women hippocampal connectivity did not vary by A? burden. For resting-state data, the interaction of gender × A? on hippocampal connectivity did not survive multiple comparison in the whole-brain analyses. In the region of interest-based analyses, resting-state hippocampal-prefrontal connectivity was positively correlated with A? load in men and was negatively correlated with A? load in women. The observed A?-related neural differences may explain the accelerated trajectory of cognitive decline and AD progression in women.

SUBMITTER: Wu M

PROVIDER: S-EPMC6584958 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Amyloid deposition is associated with different patterns of hippocampal connectivity in men versus women.

Wu Minjie M Thurston Rebecca C RC Tudorascu Dana L DL Karim Helmet T HT Mathis Chester A CA Lopresti Brian J BJ Kamboh M Ilyas MI Cohen Ann D AD Snitz Beth E BE Klunk William E WE Aizenstein Howard J HJ

Neurobiology of aging 20181201

Compared to men, women are disproportionally affected by Alzheimer's disease (AD) and have an accelerated trajectory of cognitive decline and disease progression. Neurobiological factors underlying gender differences in AD remain unclear. This study investigated brain beta-amyloid (Aβ)-related neural system differences in cognitively normal older men and women (N = 61; 41 females, 65-93 years old). We found that men and women showed different associations between Aβ load and hippocampal function ...[more]

PMID: 30711677

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Project description:BackgroundAlzheimer's disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice.MethodsAPP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior.ResultsIn APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed.ConclusionsApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.

Dataset Information

Amyloid deposition is associated with different patterns of hippocampal connectivity in men versus women.

Publications

Amyloid deposition is associated with different patterns of hippocampal connectivity in men versus women.

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