Dataset Information

Age-related loss of large dendritic spines in the precuneus is statistically mediated by proteins which are predicted targets of existing drugs

ABSTRACT: Preservation of dendritic spines is a putative mechanism of protection against cognitive impairment despite development of Alzheimer Disease (AD)-related pathologies. Aging, the chief late-onset AD risk factor, is associated with dendritic spine loss in select brain areas. However, no study to our knowledge has observed this effect in precuneus, an area selectively vulnerable to early accumulation of AD-related pathology. We therefore quantified dendritic spine density in precuneus from 98 subjects without evidence of neurocognitive decline, spanning ages 20-96, and found a significant negative correlation between age and large dendritic spine density. In these same subjects, we conducted liquid chromatography-tandem mass spectrometry of >5000 proteins and identified 203 proteins which statistically mediated the effect of age on large dendritic spine density. Using computational pharmacology, we identified 10 drugs which are predicted to target these mediators, informing future studies designed to test their effects on age-related dendritic spine loss and cognitive decline.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Matthew MacDonald

LAB HEAD: Matthew MaDonald

PROVIDER: PXD057115 | Pride | 2026-08-07

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Hom_P1_Peptide_Norm.mzML	Mzml
	Hom_P1_Peptide_Norm.mzid.gz	Mzid
	Hom_P2_Peptide_Norm.mzML	Mzml
	Hom_P2_Peptide_Norm.mzid.gz	Mzid
	Hom_P3_Peptide_Norm.mzML	Mzml

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Age-related loss of large dendritic spines in the precuneus is statistically mediated by proteins which are predicted targets of existing drugs.

Krivinko J M JM Fan P P Sui Z Z Happe C C Hensler C C Gilardi J J Ikonomovic M D MD McKinney B C BC Newman J J Ding Y Y Wang L L Sweet R A RA MacDonald M L ML

Molecular psychiatry 20241113 5

Preservation of dendritic spines is a putative mechanism of protection against cognitive impairment despite development of Alzheimer Disease (AD)-related pathologies. Aging, the chief late-onset AD risk factor, is associated with dendritic spine loss in select brain areas. However, no study to our knowledge has observed this effect in precuneus, an area selectively vulnerable to early accumulation of AD-related pathology. We therefore quantified dendritic spine density in precuneus from 98 subje ...[more]

PMID: 39537705

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Project description:The APOE gene is diversified by three alleles e2, e3, and e4 encoding corresponding apolipoprotein (apo) E isoforms. The e4 allele promotes age-related cognitive decline, risk of Alzheimer’s disease (AD), and the rate of AD dementia progression. ApoE is produced by astrocytes as high-density lipoprotein-like particles and these are internalized by neurons upon binding to neuron-expressed apoE receptors. ApoE isoforms differentially engage neuronal plasticity through poorly understood mechanisms. We examined here the effects of native apoE lipoproteins produced by immortalized astrocytes homozygous for e2, e3, and e4 alleles on the maturation and the transcriptomic profile of primary hippocampal neurons. Control neurons were grown in the presence of conditioned media from Apoe-/- astrocytes. ApoE2 and apoE3 significantly increase the dendritic arbor branching, the combined neurite length, and the total arbor surface of the hippocampal neurons, while apoE4 fails to produce similar effects and even significantly reduces the combined neurite length compared to the control. ApoE lipoproteins show no systemic effect on dendritic spine density, yet apoE2 and apoE3 increase the mature spines fraction, while apoE4 increases the immature spine fraction. This is associated with opposing effects of apoE2 or apoE3 and apoE4 on the expression of NR1 NMDA receptor subunit and PSD95. There are 1,062 genes differentially expressed across neurons cultured in the presence of apoE lipoproteins compared to the control. KEGG enrichment and gene ontology analyses show common for apoE2 and apoE3 activation of genes involved in neurite branching, and synaptic signaling. In contrast, apoE4 cultured neurons show upregulation of genes related to the glycolipid metabolism, which are involved in dendritic spine turnover and those which are usually silent in neurons and are related to cell cycle and DNA repair. In conclusion our work reveals that lipoprotein particles comprised of various apoE isoforms differentially regulate neuronal development through interaction with neuronal transcriptome. ApoE4 produces a functionally distinct transcriptomic profile, which is associated with attenuated neuronal development. Differential regulation of neuronal transcriptome by apoE isoforms is a newly identified biological mechanism, which has both implication in the development and aging of the CNS.