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Original Investigation |

Preclinical Assessment of Young Blood Plasma for Alzheimer Disease ONLINE FIRST

Jinte Middeldorp, PhD1; Benoit Lehallier, PhD1; Saul A. Villeda, PhD2,3; Suzanne S. M. Miedema, MSc1; Emily Evans1; Eva Czirr, PhD1; Hui Zhang, PhD1; Jian Luo, MD, PhD1; Trisha Stan, PhD1; Kira I. Mosher, PhD1; Eliezer Masliah, MD, PhD4,5; Tony Wyss-Coray, PhD1,6
[+] Author Affiliations
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California
2Department of Anatomy, University of California, San Francisco
3The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California
4Department of Neurosciences, University of California San Diego, La Jolla
5Department of Pathology, University of California San Diego, La Jolla
6Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
JAMA Neurol. Published online September 06, 2016. doi:10.1001/jamaneurol.2016.3185
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Importance  Alzheimer disease (AD) pathology starts long before clinical symptoms manifest, and there is no therapy to treat, delay, or prevent the disease. A shared blood circulation between 2 mice (aka parabiosis) or repeated injections of young blood plasma (plasma from 2- to 3-month-old mice) into old mice has revealed benefits of young plasma on synaptic function and behavior. However, to our knowledge, the potential benefit of young blood has not been tested in preclinical models of neurodegeneration or AD.

Objectives  To determine whether young blood plasma ameliorates pathology and cognition in a mouse model for AD and could be a possible future treatment for the disease.

Design, Setting, and Participants  In this preclinical study, mice that harbor a human mutant APP gene, which causes familial AD, were aged to develop AD-like disease including accumulation of amyloid plaques, loss of synaptic and neuronal proteins, and behavioral deficits. The initial parabiosis studies were done in 2010, and the final studies were conducted in 2014. Alzheimer disease model mice were then treated either by surgically connecting them with a young healthy mouse, thus providing a shared blood circulation through parabiosis, or through repeated injections of plasma from young mice.

Main Outcomes and Measures  Neuropathological parameters and changes in hippocampal gene expression in response to the treatment were assessed. In addition, cognition was tested in AD model mice intravenously injected with young blood plasma.

Results  Aged mutant amyloid precursor protein mice with established disease showed a near complete restoration in levels of synaptic and neuronal proteins after exposure to young blood in parabiosis (synaptophysin P = .02; calbindin P = .02) or following intravenous plasma administration (synaptophysin P < .001; calbindin P = .14). Amyloid plaques were not affected, but the beneficial effects in neurons in the hippocampus were accompanied by a reversal of abnormal extracellular receptor kinase signaling (P = .05), a kinase implicated in AD. Moreover, young plasma administration was associated with improved working memory (P = .01) and associative memory (P = .02) in amyloid precursor protein mice.

Conclusions and Relevance  Factors in young blood have the potential to ameliorate disease in a model of AD.

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Figure 1.
The Effect of Young Blood on Synaptic Activity Related Proteins in Amyloid Precursor Protein (APP) Mice

A, Schematic depicting the 3 different parabiotic pairings: wildtype (WT) isochronic, APP isochronic, and APP heterochronic. Isochronic pairs are age-matched and the same age as the APP mouse from the heterochronic pair, which is connected to a young WT mouse (2-3 months old). One cohort consisted of old male mice (16-20 months old) and another of middle-aged female mice (10-12 months old). All pairs were surgically connected for 5 weeks. B, Immunofluorescence-labeled synaptophysin in presynaptic terminals in the molecular layer of the DG of old male WT isochronic, APP isochronic, and APP heterochronic parabionts. C, Calbindin immunoreactivity in the DG of old male WT isochronic, APP isochronic, and APP heterochronic parabionts. Quantification of synaptophysin immunoreactivity (D), and calbindin immunoreactivity (E), in the molecular layer of the dentate gyrus of old male parabionts; WT isochronic (n = 6), APP isochronic (n = 6), and APP heterochronic (n = 4). F, Quantification of calbindin immunoreactivity in the molecular layer of the dentate gyrus of middle-aged female parabionts; WT isochronic (n = 9), APP isochronic (n = 11), and APP heterochronic (n = 9). All data are shown as the mean (SEM).

aP < .001, 1-way analysis of variance, Tukey post hoc test (D-F). Scale bars: 25 μm in B, and 100 μm in C.

bP < .05.

cP < .01.

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Figure 2.
Hippocampal Gene Expression Changes After Exposure to a Young Systemic Environment

A whole-genome microarray analysis was performed on the hippocampi of middle-aged female wildtype (WT) isochronic (n = 6), amyloid precursor protein (APP) isochronic (n = 7), and APP heterochronic (n = 7) parabionts. A, Heat map generated by unsupervised hierarchical clustering with a data set of genes differentially expressed between hippocampi of APP isochronic and APP heterochronic parabionts according to significance analysis of microarrays (P < .05). B, The top signaling network generated by ingenuity pathway analysis (score 35) based on the top 100 meta-ranked genes that were differentially expressed in APP isochronic and APP heterochronic parabionts (eTable 1 in the Supplement). In bold are genes that were differentially expressed in APP isochronic and APP heterochronic parabionts when analyzed in a multiple comparison analysis. C, Gene ontology analysis of the top 100 meta-ranked genes was conducted using the the online gene ontology tool DAVID for gene ontology term annotation categories biological process, molecular function, and cellular component. This graph represents all gene ontology terms with P < .05 for enrichment in the top 100 meta-ranked genes. Besides P values (gray bars), the number of genes in each category is shown. D, The top network generated by ingenuity pathway analysis (score 38) based on all differentially expressed genes that were related to calcium ion binding according to DAVID gene ontology analysis. Calcium was added (gray rectangle) to show direct interaction of many genes with this compound. Inferred molecular interactions identified by ingenuity pathway analysis are gray, down regulated genes are blue, and up regulated genes are red. Molecules for which changes were confirmed on protein level are yellow.

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Figure 3.
Effect of Administration of Young Blood Plasma on Memory Deficits in Amyloid Precursor Protein (APP) Mice

A, Schematic depicting the 4 treatment groups; wildtype (WT) or APP mice treated with either phosphate-buffered saline (PBS) or young plasma. Western blot analysis of hippocampal lysates for extracellular receptor kinase (ERK) (44/42 kDa), phosphorylated ERK (44/42 kDa) and neuron-specific enolase as loading control (B) and quantification of the ratio of phosphorylated ERK/ERK (C) (n = 8 mice per group). D, Quantification of synaptophysin immunoreactivity in the molecular layer of the dentate gyrus of WT PBS (n = 14), WT plasma (n = 13), APP PBS (n = 11), and APP plasma (n = 13) mice. E, Quantification of calbindin immunoreactivity in the molecular layer of the dentate gyrus of WT PBS (n = 15), WT plasma (n = 13), APP PBS (n = 10), and APP plasma (n = 12) mice. F, Y-maze spontaneous alternations. Dotted line represents chance level (50%). G, The total number of arm entries. H-I, Exploratory behavior monitored in a Smart-Homecage. APP mice treated with either PBS (APP PBS; n = 11) or plasma (n = 13) show no difference as measured by distance traveled, or total activity counts, over 5 minutes. J-L, Assessment of associative memory by fear conditioning. J, APP PBS or APP plasma mice exhibited similar baseline freezing time during training. K, Amygdala-dependent cued memory indicated by percentage freezing after being exposed to the conditioned tone and light in a different context 24 hours after training. L, Hippocampal-dependent learning and memory assessed by contextual fear conditioning indicated by percentage freezing in the first minute after being exposed to the same context 48 hours after training. One mouse was excluded from the APP PBS group owing to abnormal freezing behavior, corroborated by the ROUT method of identifying outliers. All data are shown as the mean (SEM).

aP < .001, 1-way analysis of variance, Tukey post hoc test (D-F). Scale bars: 25 μm in B, and 100 μm in C.

bP < .05.

cP < .01.

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