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. 2009 Mar;15(3):331-7.
doi: 10.1038/nm.1912. Epub 2009 Feb 8.

Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease

Alan H Nagahara  1 , David A Merrill, Giovanni Coppola, Shingo Tsukada, Brock E Schroeder, Gideon M Shaked, Ling Wang, Armin Blesch, Albert Kim, James M Conner, Edward Rockenstein, Moses V Chao, Edward H Koo, Daniel Geschwind, Eliezer Masliah, Andrea A Chiba, Mark H Tuszynski
Affiliations

Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease

Alan H Nagahara et al. Nat Med. 2009 Mar.

Abstract

Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimer's disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimer's disease.

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Figures

Figure 1
Figure 1. BDNF effects in APP-transgenic mice
(a) BDNF gene delivery effect on spatial memory in the Morris water maze in mutant APP-transgenic mice (TG) on distance (left) and latency (right) measures (P < 0.01 by ANOVA, *P < 0.05 by post hoc Fisher’s test, comparing TGBDNF to TGGFP). (b) BDNF effect on hippocampal-dependent (hpc.-dep.) contextual fear conditioning (P < 0.05). (c) Lentiviral gene delivery effect on gene expression (GFP reporter, left) and dense BDNF immunolabeling (black reaction product, right) in the entorhinal cortex of TGBDNF mice. (d) Axon terminals of entorhinal cortex neurons projecting into the hippocampus identified by GFP immunolabeling after entorhinal lenti-GFP injection in APP-transgenic mice (left panel, TGGFP); injection of lenti-BDNF into entorhinal neurons increases BDNF expression in the hippocampal dentate gyrus (TGBDNF), stratum lacunosum-moleculare (L–M) (**) and outer molecular layer (O, *), compared to TGGFP controls and WT mice. H, hilar region; G, granule cell layer; I, inner molecular layer (BDNF immunolabel). (e) Synaptophysin labeling in entorhinal cortex of TGBDNF mice compared to TGGFP mice. (f) Quantification of the effect of entorhinal cortex delivery of lenti-BDNF on synaptophysin immunoreactivity (SYN-IR) in both entorhinal cortex and hippocampus of APP-transgenic mice (P < 0.01 by ANOVA, *P < 0.05 by post hoc Fisher’s test comparing TGBDNF and TGGFP). (g,h) pErk immunolabeling in entorhinal cortex of TGBDNF mice compared to TGGFP mice (P < 0.001 by ANOVA, P < 0.001 by post hoc Fisher’s test comparing TGBDNF to TGGFP or WT). (i) Heat maps depicting fold changes of APP-related genes before and after treatment with BDNF. 107 probe sets are differentially expressed in entorhinal cortex of TG mice compared to WT (TG:WT), and 37 probe sets are differentially expressed in hippocampus (gray bar columns, P < 0.005 by Bayesian t-test, see Supplementary Data 1). Upregulated genes are shown in red, and downregulated genes are shown in green; color intensity corresponds to fold change in expression (Supplementary Fig. 2 and Supplementary Data 1). BDNF treatment in APP-transgenic mice (blue columns) shifts gene expression toward wild type patterns in entorhinal cortex and hippocampus. Genes are clustered by similarity; individual columns represent array samples from individual mice compared to expression in WT mice. Error bars indicate means ± s.e.m. Scale bars: c, 100 µm (left) and 200 µm (right); d, 50 µm; e, 10 µm; g, 10 µm.
Figure 2
Figure 2. BDNF effects in aged rats
(a, b) Effect of BDNF infusion into entorhinal cortex of aged rats on spatial memory in Morris water maze determined by distance (a) and latency (b) measures (P < 0.05 by ANOVA, *P < 0.05 by post hoc Fisher’s test comparing BDNF-treated to aged controls). (c) BDNF effects on search strategy in water maze after platform removal (probe trials) (P < 0.001). (d) Representative samples of search strategy during probe trials in individual rats. (e) Western blot of Erk phosphorylation and Akt phosphorylation (on Ser473, P-S473Akt) in entorhinal cortex of aged cognitively impaired rats compared to young and aged cognitively unimpaired rats; arrow indicates effect of BDNF treatment. Protein loading was standardized to Erk1/2, an abundant cellular protein. (f) Quantification of western blots (P < 0.05 by ANOVA, *P < 0.05 by post hoc Fisher’s test comparing aged cognitively impaired rats and aged cognitively impaired rats treated with vehicle to all other groups). (g) BDNF immunolabeling showing accurate targeting of infusion to entorhinal cortex (*). hpc, hippocampus. Scale bar, 1 mm. (h) Heat maps depicting fold changes of aging-related genes before and after treatment with BDNF. Genes and samples are clustered by similarity; individual columns represent array samples from individual rats compared to young rats.
Figure 3
Figure 3. BDNF effects on cell survival
(a) Fluorescent images of living cells (green, calcein label) and dead cells (red, ethidium homodimer-1 label) in cultures of postnatal day 3 entorhinal cortex neurons in control condition (no Aβ exposure), after addition of Aβ1–42 peptide (Aβ), and after addition of Aβ peptide plus 2.5 ng ml−1 BDNF. Scale bar, 50 µm. (b) Quantification of Aβ42-induced cell death after 24 h in vitro. P < 0.05 by ANOVA, * indicates the difference between the vehicle- and BDNF-treated groups and the Aβ group, P < 0.001 by Fisher’s post hoc test. (c) Perforant path lesion model: GFP immunolabeling in entorhinal cortex at site of lenti-GFP vector injection (left) and BDNF protein production (region of dark immunolabeling) in the same region (right). I–VI indicates cortical laminae. Scale bar, 150 µm. (d,e) Perforant path lesion causes significant loss of Nissl-stained neurons in layer II of the entorhinal cortex (EC) in GFP-injected controls (P < 0.01 versus intact). Nissl stain of layer II entorhinal cortex after perforant path lesions in GFP-injected controls (Lesion-GFP) and BDNF-treated rats (Lesion-BDNF) is shown in d. Stereological quantification of cell number and size after perforant path lesions is shown in e (left, P < 0.05 by ANOVA, *P < 0.01 BDNF versus GFP and NGF by Fisher’s post hoc test; right, P < 0.01 by ANOVA, *P < 0.05 BDNF versus GFP and NGF by post hoc Fisher’s test). Scale bar, 25 µm. (f) pAKT label in entorhinal cortex of treated versus control perforant path–lesioned rats, with stereological quantification at right. Scale bar, 10 µm (*P < 0.001).
Figure 4
Figure 4. BDNF effects in primates
(a) Nissl stain of layer II entorhinal cortex neuronal death induced by perforant path lesion and neuroprotection by lenti-BDNF injection. Scale bar, 65 µm. (b) Stereological quantification showing loss of layer II entorhinal cortex neurons after perforant path lesions and protection of neurons by injection of lenti-BDNF (P < 0.01 by ANOVA, *P < 0.01 by Fisher’s post hoc test compared to lesion controls). (c) GFP immunolabeling in entorhinal cortex (EC, left) and BDNF protein expression (right, BDNF immunolabel) following injection of lenti-BDNF vector in aged, cognitively impaired monkeys. AB, angular bundle (dashed lines). Scale bar, 75 µm. (d) BDNF immunolabeling in hippocampal dentate gyrus (DG) and hippocampal regions CA3 and CA1 in control aged subjects injected with lenti-GFP in entorhinal cortex (left); BDNF increases after lenti-BDNF injection (right). Scale bar, 250 µm. (e) Nissl stain showing hypertrophy of neurons in aged monkey entorhinal cortex after BDNF gene delivery. Scale bar, 35 µm. (f) Quantification of neuronal size in aged monkeys (*P < 0.01 by t-test). (g) Visuospatial discrimination task used to test cognitive function in aged monkeys (details in text). (h) Quantification of preoperative choice accuracy in aged and young monkeys before treatment (left; P < 0.01 by ANOVA, *P < 0.01 both aged groups compared to young) and proportional improvement in performance after lenti-GFP or lenti-BDNF gene delivery to entorhinal cortex (right; *P < 0.05, two-tailed t-test).
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References

    1. Gomez-Isla T, et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J. Neurosci. 1996;16:4491–4500. - PMC - PubMed
    1. Kordower JH, et al. Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann. Neurol. 2001;49:202–213. - PubMed
    1. Price JL. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch. Neurol. 2001;58:1395–1402. - PubMed
    1. Squire LR, Kandel ER. Memory. New York: Scientific American Library; 2000. Chapter 5.
    1. Yan Q, et al. Immunocytochemical localization of TrkB in the central nervous system of the adult rat. J. Comp. Neurol. 1997;378:135–137. - PubMed

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