Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease
Open accessAbstract
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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Written from the paper’s full text.
TL;DR
Entorhinal BDNF delivery produced broad neuroprotective and restorative effects in rodent and primate models related to Alzheimer’s disease, including improved learning/memory and reversal of neuronal atrophy. These benefits occurred independently of direct modulation of insoluble amyloid plaque load.
Key findings
- In J20 APP-transgenic mice treated after disease onset, entorhinal BDNF gene delivery improved spatial memory versus GFP controls (P < 0.01 by ANOVA; P < 0.05 by Fisher’s test), restored synaptic markers (P < 0.05), increased Erk phosphorylation (P < 0.001), and normalized 55% of dysregulated genes; it did not affect neuronal number or amyloid plaque density.
- In aged cognitively impaired rats, 28-day entorhinal BDNF infusion (120 ng/day/side) improved water maze distance, latency, and platform crossings (P < 0.05), restored Erk phosphorylation, and induced at least 30% normalization in 43% of entorhinal and 42% of hippocampal age-related genes.
- BDNF prevented Aβ1–42–induced death of cultured rat entorhinal neurons (P < 0.05), while NGF had no effect; in rats with perforant path lesions, BDNF prevented the typical 20% loss of layer II entorhinal neurons (P < 0.01), ameliorated atrophy (P < 0.05), and increased phospho-AKT.
- In primates, perforant path lesions caused 45.9 ± 8.5% loss of lateral entorhinal layer II neurons, whereas BDNF maintained 85.4 ± 7.1% of neurons (P < 0.01); in aged monkeys, BDNF improved visuospatial performance by the tenth postoperative session (P < 0.05) and increased mean entorhinal neuronal size (P < 0.01).
Methods
- Multiple models were used: J20 mutant APP transgenic mice, aged Fischer rats, primary rat entorhinal cortex cultures, adult rats and rhesus monkeys with perforant path lesions, and aged rhesus monkeys.
- Interventions included lentiviral BDNF-GFP or GFP delivery into entorhinal cortex, recombinant BDNF protein infusion, and control treatments; outcomes included Morris water maze, fear conditioning, visuospatial discrimination, stereological neuron counts/size, immunolabeling, western blotting, and gene expression arrays.
- Statistical analyses used Student’s t-tests, ANOVA with Fisher post hoc tests, and Bayesian modified t-tests for arrays with significance at P < 0.005; experimental manipulations and data analysis were blinded.
Limitations
- Stated: amyloid oligomers were not measured; after primate perforant path lesions, cognitive performance was not assessed because axonal regeneration and reinnervation of hippocampal targets do not occur in that model.
- Stated: prior growth factor translation has been limited by lack of methods for effective, safe, sustained nervous system delivery, although this study demonstrated efficacy with two delivery methods.
- Evident: the findings are preclinical across rodent and primate models, with small group sizes in several experiments, and no human clinical outcomes or long-term safety data are reported.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 42 cited sources checked · 0 supported · 0 flagged
- Findingown data
Hippocampal-independent fear conditioning was not impaired in either transgenic mouse group.
“Hippocampal-independent fear conditioning was not impaired in either transgenic mouse group (Supplementary Fig. 1a), as expected.”
Quote in the paperNot a substantial claim - Findingown data
Immunolabeling confirmed high amounts of BDNF in the entorhinal cortices of TGBDNF mice.
“Immunolabeling confirmed high amounts of BDNF in the entorhinal cortices of TGBDNF mice (Fig. 1c).”
Quote in the paperSubstantial claim - Findingown data
Eighty-one percent of aged rats showed baseline cognitive impairment.
“Eighty-one percent of aged rats showed baseline cognitive impairment and then received bilateral, 28-d infusions of either recombinant BDNF protein (120 ng per day per side) or vehicle (artificial cerebrospinal fluid) into the medial entorhinal cortex.”
Quote in the paperSubstantial claim - Findingown data
Entorhinal BDNF gene delivery improved APP-related alterations in gene expression in 55% of dysregulated genes in transgenic mice.
“Notably, entorhinal BDNF gene delivery improved APP-related alterations in gene expression in 55% of dysregulated genes in transgenic mice (Fig. 1i, Supplementary Fig. 2 and Supplementary Data 1).”
Quote in the paperSubstantial claim - Findingown data
Performance of TGBDNF mice did not differ significantly from WT littermate controls in spatial memory.
“The performance of TGBDNF mice did not differ significantly from WT littermate controls (Fig. 1a).”
Quote in the paperSubstantial claim
- Findingown data
BDNF induced significant recovery of synaptic markers in both entorhinal cortex and dentate gyrus of transgenic mice.
“BDNF induced significant recovery of synaptic markers in both entorhinal cortex and dentate gyrus of transgenic mice (P < 0.05; Fig. 1e,f).”
Quote in the paperSubstantial claim - Findingown data
In J20 mice, BDNF gene delivery after disease onset ameliorates spatial memory deficits compared to GFP controls.
“Over five successive daily blocks of trials, significant amelioration of spatial memory deficits occurred in TGBDNF mice compared to TGGFP mice (P < 0.01 by analysis of variance (ANOVA); P < 0.05 by post hoc Fisher’s test comparing TGBDNF to TGGFP; Fig. 1a).”
Quote in the paperSubstantial claim - Findingown data
In hippocampal-dependent fear conditioning, TGGFP mice showed trends toward impaired performance compared to WT mice.
“In the hippocampal-dependent aspect of the task, TGGFP mice showed trends toward impaired performance compared to WT mice (P < 0.05 by ANOVA; P = 0.12 by post hoc Fisher’s test comparing TGGFP versus WT mice).”
Quote in the paperSubstantial claim - Findingown data
Functional impairment with aging was associated with significant reductions in entorhinal concentrations of phosphorylated Erk.
“Functional impairment with aging was associated with significant reductions in entorhinal concentrations of phosphorylated Erk (P < 0.05 by ANOVA; *P < 0.05 by post hoc Fisher’s test for aged cognitively impaired rats versus aged cognitively unimpaired rats and young rats);”
Quote in the paperSubstantial claim - Findingown data
BDNF treatment significantly increased Erk phosphorylation in transgenic mice.
“BDNF treatment also significantly increased extracellular signal–related kinase (Erk) phosphorylation, thereby augmenting cell signaling related to the functional state of neurons (P < 0.001; Fig. 1g,h).”
Quote in the paperNot a substantial claim - Findingown data
Substantial trafficking of BDNF into hippocampal regions CA1-3 and dentate gyrus occurred in TGBDNF mice.
“Furthermore, substantial trafficking of BDNF into hippocampal regions CA1–3 and dentate gyrus occurred (Fig. 1d).”
Quote in the paperSubstantial claim - Findingown data
After BDNF treatment, aged cognitively impaired rats showed marked improvement in search strategy.
“After BDNF treatment, aged cognitively impaired rats showed marked improvement in search strategy, with greater swimming around the platform location (Fig. 2d).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of mutant APP perturbed normal patterns of entorhinal cortex and hippocampal gene expression, with dysregulation of canonical pathways related to oxidative stress and lipid metabolism.
“Overexpression of mutant APP perturbed normal patterns of entorhinal cortex and hippocampal gene expression, with dysregulation of canonical pathways related to oxidative stress and lipid metabolism, among other pathways (Supplementary Fig. 2 and Supplementary Data 1).”
Quote in the paperNot a substantial claim - Findingown data
BDNF treatment initiated after disease onset affected neither neuronal number nor amyloid plaque density in J20 mice.
“Notably, BDNF treatment initiated after disease onset affected neither neuronal number nor amyloid plaque density (Supplementary Fig. 1b–d)”
Quote in the paperSubstantial claim - Findingown data
Restorative effects of BDNF on array profiles were also observed in hippocampus.
“The restorative effects of BDNF on array profiles were also observed in hippocampus (Fig. 1i and Supplementary Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
TGBDNF mice performed significantly better than TGGFP mice on hippocampal-dependent fear conditioning.
“TGBDNF mice performed significantly better than TGGFP mice on this task (P < 0.05; Fig. 1b).”
Quote in the paperSubstantial claim - Findingown data
Alterations in the PI3K-Akt pathway were not associated with age-related impairment in the water maze.
“Alterations in the cell survival phosphoinositide-3 kinase–Akt pathway were not associated with age-related impairment in the water maze (Fig. 2e)”
Quote in the paperSubstantial claim - Findingown data
Primary entorhinal cortex neurons from postnatal day 3 rats exposed to toxic Aβ1-42 peptide in vitro resulted in cell death within 24 h.
“First, primary entorhinal cortex neurons from postnatal day 3 rats were exposed to the toxic Aβ1–42 peptide in vitro, resulting in cell death within 24 h (Fig. 3a,b).”
Quote in the paperSubstantial claim - Findingown data
Aging was associated with altered patterns of gene expression compared to young rats in both the entorhinal cortex (61 probe sets) and hippocampus (181 probe sets).
“Aging was associated with altered patterns of gene expression compared to young rats in both the entorhinal cortex (61 probe sets) and hippocampus (181 probe sets) (Fig. 2h; P < 0.005 by Bayesian t-test, see also Supplementary Fig. 3 and Supplementary Data 2 online), consistent with previous reports18.”
Quote in the paperSubstantial claim - Findingown data
Infusion of BDNF restored Erk phosphorylation to levels not differing from young and aged cognitively unimpaired rats.
“infusion of BDNF restored Erk phosphorylation to levels not differing from those in young and aged cognitively unimpaired rats (Fig. 2e,f).”
Quote in the paperSubstantial claim - Findingown data
Entorhinal cortex BDNF delivery induced at least a 30% change toward normalization in 43% of entorhinal age-related genes and 42% of hippocampal genes.
“Entorhinal cortex BDNF delivery induced at least a 30% change toward normalization in 43% of entorhinal age-related genes and 42% of hippocampal genes (P < 0.005, Fig. 2h and Supplementary Data 2).”
Quote in the paperSubstantial claim - Findingown data
NGF had no effect on Aβ1-42-induced neuron death in vitro.
“Nerve growth factor (NGF) had no effect (Fig. 3b; cortical neurons do not express the NGF receptor TrkA19).”
Quote in the paperSubstantial claim - Findingown data
Control GFP- and NGF-treated rats showed significant 20% loss of stereologically quantified neurons in layer II of the entorhinal cortex compared to the contralateral side.
“Two weeks after the lesions were made, control GFP- and NGF-treated rats showed a significant 20% loss of stereologically quantified neurons in layer II of the entorhinal cortex compared to the contralateral side of the brain (P < 0.05 by ANOVA; P < 0.05 by post hoc Fisher’s test comparing intact to lesioned control rats; Fig. 3c–e).”
Quote in the paperSubstantial claim - Findingown data
BDNF treatment concurrent with Aβ1-42 exposure prevented neuron death in vitro.
“BDNF treatment concurrent with Aβ1–42 exposure prevented neuron death (P < 0.05; Fig. 3a,b).”
Quote in the paperSubstantial claim - Findingown data
BDNF significantly prevented lesion-induced entorhinal neuronal death in monkeys, maintaining 85.4 ± 7.1% of neurons on the lesioned side compared to intact subjects.
“BDNF significantly prevented lesion-induced entorhinal neuronal death (P < 0.01), maintaining 85.4 ± 7.1% of neurons on the lesioned side compared to intact subjects (Fig. 4b).”
Quote in the paperSubstantial claim - Findingown data
Perforant path lesions without BDNF treatment resulted in loss of 45.9 ± 8.5% of neurons in layer II of the entorhinal cortex in the lateral region relative to intact monkeys.
“Stereological quantification revealed that perforant path lesions without BDNF treatment resulted in the loss of 45.9 ± 8.5% of neurons in layer II of the entorhinal cortex in the lateral region relative to those in intact monkeys (Fig. 4a,b).”
Quote in the paperSubstantial claim - Findingown data
BDNF-treated aged monkeys showed significant improvement in performance compared to control aged monkeys by the tenth postoperative session.
“BDNF-treated aged monkeys showed a significant improvement in performance compared to control aged monkeys by the tenth postoperative session (P < 0.05, Fig. 4h).”
Quote in the paperSubstantial claim - Findingown data
All aged monkeys showed significantly impaired visuospatial learning compared to young monkeys.
“All aged monkeys showed significantly impaired visuospatial learning compared to young monkeys (P < 0.01; Fig. 4g,h).”
Quote in the paperSubstantial claim - Findingown data
BDNF prevented cell death in the rat perforant path lesion model.
“BDNF prevented cell death (Fig. 3d; P < 0.01)”
Quote in the paperSubstantial claim - Findingown data
BDNF significantly increased expression of phospho-AKT in entorhinal cortex neurons.
“BDNF also significantly increased expression of phospho-AKT, a marker of canonical cell survival pathways6, in entorhinal cortex neurons (Fig. 3f).”
Quote in the paperSubstantial claim - Findingown data
BDNF ameliorated cell atrophy in the rat perforant path lesion model.
“and ameliorated cell atrophy (Fig. 3e; P < 0.05).”
Quote in the paperSubstantial claim - Findingown data
Mean entorhinal neuronal size significantly increased in BDNF-treated monkeys compared to monkeys receiving lenti-GFP.
“Furthermore, mean entorhinal neuronal size significantly increased in BDNF-treated monkeys compared to monkeys receiving lenti-GFP (P < 0.01; Fig. 4e,f).”
Quote in the paperSubstantial claim - Premisecitation
J20 transgenic mice express the human amyloid precursor protein transgene bearing both the Swedish and the Indiana APP mutations.
“J20 transgenic mice express the human amyloid precursor protein (APP) transgene bearing both the Swedish and the Indiana APP mutations10.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Mucke, L. et al. High-level neuronal expression of aβ 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000). source
Not checked in the free run.
- Premisecitation
Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease.
“Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer’s disease1–3.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Gomez-Isla, T. et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 16, 4491–4500 (1996). source
Not checked in the free run.
- cites [2] Kordower, J.H. et al. Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann. Neurol. 49, 202–213 (2001). source
Not checked in the free run.
- cites [3] Price, J.L. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch. Neurol. 58, 1395–1402 (2001). source
Not checked in the free run.
- Premisecitation
Amounts of BDNF protein are reduced in the entorhinal cortex and hippocampus in Alzheimer's disease.
“Furthermore, amounts of BDNF protein are reduced in the entorhinal cortex and hippocampus in Alzheimer’s disease7–9.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [7] Narisawa-Saito, M., Wakabayashi, K., Tsuji, S., Takahashi, H. & Nawa, H. Regional specificity of alterations in NGF, BDNF and NT-3 levels in Alzheimer's disease. Neuroreport 7, 2925–2928 (1996). source
Not checked in the free run.
- cites [8] Connor, B. et al. Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Brain Res. Mol. Brain Res. 49, 71–81 (1997). source
Not checked in the free run.
- cites [9] Hock, C., Heese, K., Hulette, C., Rosenberg, C. & Otten, U. Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch. Neurol. 57, 846–51 (2000). source
Not checked in the free run.
- Premisecitation
Aging is accompanied by marked declines in cognitive function associated with the entorhinal cortex.
“Aging is accompanied by marked declines in cognitive function associated with the entorhinal cortex15”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Morrison, J.H. & Hof, P.R. Life and death of neurons in the aging brain. Science 278, 412–419 (1997). source
Not checked in the free run.
- Premisecitation
Cell death is not a mechanism underlying age-related cognitive decline.
“cell death is not a mechanism underlying this decline16,17.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16] Merrill, D.A., Chiba, A.A. & Tuszynski, M.H. Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats. J. Comp. Neurol. 438, 445–456 (2001). source
Not checked in the free run.
- cites [17] Merrill, D.A., Roberts, J.A. & Tuszynski, M.H. Conservation of neuron number and size in entorhinal cortex layers II, III and V/VI of aged primates. J. Comp. Neurol. 422, 396–401 (2000). source
Not checked in the free run.
- Interpretationown data
The ameliorative effects of BDNF in J20 mice are exerted independently of direct modulation of insoluble Aβ.
“indicating that the ameliorative effects of BDNF in this model are exerted independently of direct modulation of insoluble β-amyloid (Aβ; amyloid oligomers were not measured).”
Quote in the paperSubstantial claim- Rests on an assumption: Insoluble amyloid plaque density is a sufficient measure of direct amyloid modulation for concluding that BDNF effects are amyloid-independent.
- Interpretationown data
BDNF, acting independently of direct effects on insoluble Aβ, improved genetic, molecular, synaptic and behavioral parameters of APP-transgenic mice when treatment was initiated after disease onset.
“Thus, BDNF, acting independently of direct effects on insoluble Aβ, improved genetic, molecular, synaptic and behavioral parameters of APP-transgenic mice when treatment was initiated after disease onset.”
Quote in the paperSubstantial claim - Premisecitation
Perforant path transections typically induce death in 20% of neurons in layer II of the entorhinal cortex.
“we subjected rats to perforant path transections that typically induce death in 20% of neurons in layer II of the entorhinal cortex20.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Peterson, D.A., Lucidi-Phillipi, C.A., Eagle, K.L. & Gage, F.H. Perforant path damage results in progressive neuronal death and somal atrophy in layer II of entorhinal cortex and functional impairment with increasing postdamage age. J. Neurosci. 14, 6872–6885 (1994). source
Not checked in the free run.
- Premisecitation
Growth factor-mediated prevention of neuronal loss in transection models has predicted protection from disease-specific mechanisms in other models.
“Indeed, growth factor–mediated prevention of neuronal loss in transection models has predicted protection from disease-specific mechanisms in other models22–25.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [22] Tomac, A. et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373, 335–339 (1995). source
Not checked in the free run.
- cites [23] Winkler, C., Sauer, H., Lee, C.S. & Bjorklund, A. Short-term GDNF treatment provides long-term rescue of lesioned nigral dopaminergic neurons in a rat model of Parkinson's disease. J. Neurosci. 16, 7206–7215 (1996). source
Not checked in the free run.
- cites [24] Gash, D.M. et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380, 252–255 (1996). source
Not checked in the free run.
- cites [25] Kaspar, B.K., Llado, J., Sherkat, N., Rothstein, J.D. & Gage, F.H. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301, 839–842 (2003). source
Not checked in the free run.
- Interpretationown data
Entorhinal cortex BDNF administration compensates for genetic, molecular and behavioral parameters of age-related neural dysfunction.
“Thus, entorhinal cortex BDNF administration compensates for genetic, molecular and behavioral parameters of age-related neural dysfunction.”
Quote in the paperSubstantial claim - Premisecitation
Concentrations of BDNF decline in the entorhinal cortex and hippocampus in Alzheimer's disease.
“Notably, the concentrations of BDNF decline in the entorhinal cortex and hippocampus in Alzheimer’s disease7–9”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [7] Narisawa-Saito, M., Wakabayashi, K., Tsuji, S., Takahashi, H. & Nawa, H. Regional specificity of alterations in NGF, BDNF and NT-3 levels in Alzheimer's disease. Neuroreport 7, 2925–2928 (1996). source
Not checked in the free run.
- cites [8] Connor, B. et al. Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Brain Res. Mol. Brain Res. 49, 71–81 (1997). source
Not checked in the free run.
- cites [9] Hock, C., Heese, K., Hulette, C., Rosenberg, C. & Otten, U. Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch. Neurol. 57, 846–51 (2000). source
Not checked in the free run.
- Interpretationown data
Therapeutic effects of BDNF extend across multiple animal models of Alzheimer's disease, including mutant amyloid mice, aged rats and adult perforant path-lesioned rats.
“The therapeutic effects of BDNF extend across multiple animal models of Alzheimer’s disease, including mutant amyloid mice, aged rats and adult perforant path–lesioned rats.”
Quote in the paperSubstantial claim - Interpretationown data
This study demonstrates extensive trophic actions of BDNF on neurons of the entorhinal cortex, and via anterograde transport, the hippocampus.
“This study demonstrates the extensive trophic actions of BDNF on neurons of the entorhinal cortex, and, via anterograde transport, the hippocampus.”
Quote in the paperSubstantial claim - Premisecitation
A lack of methods for effectively and safely delivering growth factors to the nervous system over sustained time periods has been a major factor limiting their translational testing.
“A lack of methods for effectively and safely delivering growth factors to the nervous system over sustained time periods has been a major factor limiting their translational testing32.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Thoenen, H. & Sendtmer, M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nat. Neurosci. 5, 1046–1050 (2002). source
Not checked in the free run.
- Interpretationreasoning
Taken together, these results establish a rationale for BDNF delivery to the entorhinal cortex as a means for treating entorhinal and hippocampal degeneration in Alzheimer's disease.
“Taken together, these results establish a rationale for BDNF delivery to the entorhinal cortex as a means for treating entorhinal and hippocampal degeneration in Alzheimer’s disease.”
Quote in the paperSubstantial claim- Rests on an assumption: Efficacy of BDNF in the animal models used in this study predicts therapeutic benefit in human Alzheimer's disease.
- May combine two claims. 18
- Classified as probably not a substantial claim. 4
May combine two claims.
Findingown dataAnalysis of brain sections showed accurate targeting of lentiviral vectors to the entorhinal cortex and elevated BDNF protein distribution in the hippocampus, suggesting anterograde transport.
“Analysis of brain sections showed accurate targeting of lentiviral vectors to the entorhinal cortex and elevated BDNF protein distribution in the hippocampus, suggesting anterograde transport (Fig. 4c,d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOur experiment demonstrated efficacy using both treatment methods (protein infusion and gene delivery).
“Our experiment demonstrated efficacy using both treatment methods.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationBDNF and its receptor TrkB are widely expressed in the entorhinal cortex, and BDNF is anterogradely trafficked into the hippocampus.
“BDNF and its receptor, tyrosine receptor kinase B (TrkB), are widely expressed in the entorhinal cortex, and BDNF is anterogradely trafficked into the hippocampus5”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Yan, Q. et al. Immunocytochemical localization of TrkB in the central nervous system of the adult rat. J. Comp. Neurol. 378, 135–137 (1997). source
Not checked in the free run.
May combine two claims.
PremisecitationBeginning at age 2-3 months, J20 mice show cortical plaques and progressive cell loss in the entorhinal cortex and show cognitive decline by 6-7 months of age.
“Beginning at age 2–3 months, these mice show cortical plaques and progressive cell loss in the entorhinal cortex and show cognitive decline by 6–7 months of age10,11.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Mucke, L. et al. High-level neuronal expression of aβ 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000). source
Not checked in the free run.
- cites [11] Palop, J.J. et al. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc. Natl. Acad. Sci. USA 100, 9572–9577 (2003). source
Not checked in the free run.
May combine two claims.
PremisecitationAlzheimer's disease affects the entorhinal cortex profoundly and early, contributing to cardinal symptoms of short-term memory loss.
“The most common age-related neurodegenerative disorder, Alzheimer’s disease, affects the entorhinal cortex profoundly and early in the disease, contributing to cardinal symptoms of short-term memory loss1–3.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Gomez-Isla, T. et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 16, 4491–4500 (1996). source
Not checked in the free run.
- cites [2] Kordower, J.H. et al. Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann. Neurol. 49, 202–213 (2001). source
Not checked in the free run.
- cites [3] Price, J.L. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch. Neurol. 58, 1395–1402 (2001). source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationThe entorhinal cortex is a primary source of inputs to the hippocampus and exerts a key influence in learning and memory.
“The entorhinal cortex is a primary source of inputs to the hippocampus, exerting a key influence in learning and memory4.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Squire, L.R. & Kandel, E.R. Memory Chapter 5 (Scientific American Library, New York, 2000).
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBDNF in the hippocampus is implicated in plasticity mechanisms hypothesized to underlie learning.
“where it is implicated in plasticity mechanisms hypothesized to underlie learning6.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Kaplan, D.R. & Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391 (2000). source
Not checked in the free run.
May combine two claims.
Interpretationown dataBDNF specifically prevented Aβ1-42-induced cell death, because BDNF did not increase neuron number in naive entorhinal cultures.
“BDNF specifically prevented Aβ1–42–induced cell death, because BDNF did not increase neuron number in naive entorhinal cultures (Supplementary Fig. 4 online).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDeficiencies in Erk-MAPKK, but not Akt, would be predicted in a model of cell dysfunction but not death, and findings in aged rats are consistent with this prediction.
“Deficiencies in canonical signaling through Erk–mitogen-activated protein kinase kinase, but not Akt, would be predicted in a model of cell dysfunction but not death6; our findings in aged rats are consistent with this prediction, as BDNF ameliorates age-related deficiencies in Erk without detectably perturbing Akt.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Kaplan, D.R. & Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391 (2000). source
Not checked in the free run.
May combine two claims.
PremisecitationCell death in the perforant path transection model occurs independently of Alzheimer's disease-related Aβ toxicity and neurofibrillary degeneration, but final mechanisms of caspase activation and mitochondrial calcium release are common to apoptotic and necrotic cell death.
“Although the cell death in this model occurs independently of Alzheimer’s disease–related Aβ toxicity and neurofibrillary degeneration, the final mechanisms of caspase activation and mitochondrial calcium release are common to apoptotic and necrotic cell death21.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Rohn, T.T., Rissman, R.A., Head, E. & Cotman, C.W. Caspase activation in the Alzheimer's disease brain: tortuous and torturous. Drug News Perspect. 15, 549–557 (2002). source
Not checked in the free run.
May combine two claims.
PremisecitationExtensive cell death does not occur in the aged primate entorhinal cortex with aging, consistent with findings in aged rodents.
“Extensive cell death does not occur in the aged primate entorhinal cortex with aging17,26, consistent with findings in aged rodents16.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [17] Merrill, D.A., Roberts, J.A. & Tuszynski, M.H. Conservation of neuron number and size in entorhinal cortex layers II, III and V/VI of aged primates. J. Comp. Neurol. 422, 396–401 (2000). source
Not checked in the free run.
- cites [26] Gazzaley, A.H., Thakker, M.M., Hof, P.R. & Morrison, J.H. Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys. Neurobiol. Aging 18, 549–553 (1997). source
Not checked in the free run.
- cites [16] Merrill, D.A., Chiba, A.A. & Tuszynski, M.H. Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats. J. Comp. Neurol. 438, 445–456 (2001). source
Not checked in the free run.
May combine two claims.
PremisecitationThe aged primate is the best available model of age-related neurodegeneration in humans, showing cognitive decline with aging and reductions in neuronal function.
“The aged primate is the best available model of age-related neurodegeneration in humans, showing cognitive decline with aging and reductions in neuronal function15.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Morrison, J.H. & Hof, P.R. Life and death of neurons in the aging brain. Science 278, 412–419 (1997). source
Not checked in the free run.
May combine two claims.
PremisecitationBDNF influences neuronal plasticity by facilitating neurotransmitter release, increasing vesicular docking, enhancing glutamate-evoked post-synaptic responses and facilitating hippocampal and cortical long-term potentiation.
“BDNF influences neuronal plasticity by facilitating neurotransmitter release29, increasing vesicular docking, enhancing glutamate-evoked post-synaptic responses30 and facilitating hippocampal and cortical long-term potentiation31.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [29] Stoop, R. & Poo, M.M. Synaptic modulation by neurotrophic factors. Prog. Brain Res. 109, 359–364 (1996). source
Not checked in the free run.
- cites [30] Levine, E.S., Crozier, R.A., Black, I.B. & Plummer, M.R. Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-d-aspartic acid receptor activity. Proc. Natl. Acad. Sci. USA 95, 10235–10239 (1998). source
Not checked in the free run.
- cites [31] Figurov, A., Pozzo-Miller, L.D., Olafsson, P., Wang, T. & Lu, B. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709 (1996). source
Not checked in the free run.
May combine two claims.
PremisecitationBDNF is produced in the entorhinal cortex throughout life and undergoes anterograde trafficking into the hippocampus.
“BDNF is produced in the entorhinal cortex throughout life and it undergoes anterograde trafficking into the hippocampus5.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Yan, Q. et al. Immunocytochemical localization of TrkB in the central nervous system of the adult rat. J. Comp. Neurol. 378, 135–137 (1997). source
Not checked in the free run.
May combine two claims.
Interpretationown dataThis approach acts independently of direct modulation of amyloid, providing a key alternative to, and potential synergy with, amyloid-modifying treatments.
“This approach acts independently of direct modulation of amyloid, providing a key alternative to, and potential synergy with, amyloid-modifying treatments.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIntraventricular infusions of growth factors typically fail to reach most neurons, and hence recent clinical trials used intraparenchymal infusions or gene delivery.
“Intraventricular infusions of growth factors typically fail to reach most neurons33, and hence recent clinical trials used intraparenchymal infusions or gene delivery34–37.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [33] Kordower, J.H. et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease. Ann. Neurol. 46, 419–424 (1999). source
Not checked in the free run.
- cites [34] Gill, S.S. et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med. 9, 589–595 (2003). source
Not checked in the free run.
- cites [35] Tuszynski, M.H. et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 11, 551–555 (2005). source
Not checked in the free run.
- cites [36] Marks, W.J., Jr. et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial. Lancet Neurol. 7, 400–408 (2008). source
Not checked in the free run.
- cites [37] Kaplitt, M.G. et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial. Lancet 369, 2097–2105 (2007). source
Not checked in the free run.
May combine two claims.
Interpretationown dataEffects of BDNF extend to primate models, which show amelioration of cell death, enhancement of cell size and improvement in age-related cognitive decline in response to BDNF.
“Furthermore, these effects extend to primate models, which show amelioration of cell death, enhancement of cell size and improvement in age-related cognitive decline in response to BDNF.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMechanisms underlying these actions include normalization of gene expression patterns in models of disease and aging, augmentation of intracellular signaling related to the functional state of the cell and enhancement of synaptic marker expression.
“The mechanisms underlying these actions include normalization of gene expression patterns in models of disease and aging, augmentation of intracellular signaling related to the functional state of the cell and enhancement of synaptic marker expression.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBDNF administration in these models prevents cell death, reverses neuronal atrophy and ameliorates behavioral deficits.
“BDNF administration in these models prevents cell death, reverses neuronal atrophy and ameliorates behavioral deficits.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningThe potency of BDNF in the preclinical models presented here, including its validation in primate models, provides a rationale for exploring clinical translation.
“The potency of BDNF in the preclinical models presented here, including its validation in primate models, provides a rationale for exploring clinical translation.”
Quote in the paperSubstantial claim- Rests on an assumption: Efficacy of BDNF in the animal models used in this study predicts therapeutic benefit in human Alzheimer's disease.
Classified as probably not a substantial claim.
Study design and conductnone givenExperimental manipulations and data analysis in this and all subsequent studies were conducted in a blinded fashion.
“Experimental manipulations and data analysis in this and all subsequent studies were conducted in a blinded fashion.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Efficacy of BDNF in the animal models used in this study predicts therapeutic benefit in human Alzheimer's disease.
“Taken together, these results establish a rationale for BDNF delivery to the entorhinal cortex as a means for treating entorhinal and hippocampal degeneration in Alzheimer’s disease.”
The paper relies on this without support.
Insoluble amyloid plaque density is a sufficient measure of direct amyloid modulation for concluding that BDNF effects are amyloid-independent.
“indicating that the ameliorative effects of BDNF in this model are exerted independently of direct modulation of insoluble β-amyloid (Aβ; amyloid oligomers were not measured).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Driving BDNF levels up improves learning and memory deficits in preclinical models of AD.
“and driving BDNF levels up improves learning and memory deficits in preclinical models of AD”
From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [39]
Experimental BDNF therapy has promising results in animal models of Alzheimer's disease, Parkinson's disease, and major depressive disorder.
“experimental therapy has been investigated in vivo and in vitro with promising results in animal models of AD [197], PD [198], and MDD [199]”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [197]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Aged-monkey task has conflicting numbers of choices
MajorThe results describe a two-choice visuospatial task, but the Methods say that three choice objects were presented.
“the monkeys underwent testing on a two-choice version of the task (Fig. 4g)”
“after a 2-s delay, three choice objects were presented. The monkey was required to choose the original object.”
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- Authors
- Nagahara, A. H., Merrill, D. A., Coppola, G., Tsukada, S., Schroeder, B. E., Shaked, G. M., Wang, L., Blesch, A., Kim, A., Conner, J. M., Rockenstein, E., Chao, M. V., Koo, E. H., Geschwind, D., Masliah, E., Chiba, A. A., & Tuszynski, M. H.
- Affiliations
- University of California San Diego (US)
- University of California, Los Angeles (US)
- New York University (US)
- Veterans Health Administration (US)
- Corresponding author
- Tuszynski, Mark H
- ORCID
- Venue
- Nature Medicine
- Published
- 2009-02-08
- Volume
- 15
- Issue
- 3
- Pages
- 331-337
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2838375
- OpenAlex
- W2071610467
- Semantic Scholar
- 927ffcf0d1fefa93b088dd0aaac12a1fbdc3b465
- Cited by
- 1,034
- References
- 38
- Citations by year
- 2026: 33 · 2025: 50 · 2024: 61 · 2023: 60 · 2022: 56 · 2021: 62 · 2020: 56 · 2019: 49 · 2018: 50 · 2017: 52 · 2016: 69 · 2015: 68 · 2014: 79 · 2013: 83 · 2012: 61
- FWCI
- 45.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- University of California, Davis
- University of California, Irvine
- National Institute on Aging (P01AG010435, R37AG018440, P01AG022074, AG10435)
- California National Primate Research Center
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- brain-derived neurotrophic factor, Alzheimer's disease, neuroprotection, entorhinal cortex, hippocampus, synaptic loss, gene expression, learning and memory, cognitive decline, aging, neuronal atrophy, nonhuman primate model, gene delivery
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Mice, Transgenic, Primates, Neuroprotective Agents, Brain-Derived Neurotrophic Factor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
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