Defects in synaptic development and plasticity may lead to autism. Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptogenesis and synaptic plasticity. BDNF is synthesized as a precursor, pro-BDNF, which can be processed into either a truncated form or into mature BDNF. Previous studies reported increased BDNF-immunoreactive protein in autism, but the mechanism of this increase has not been investigated. We examined BDNF mRNA by real-time reverse transcription-polymerase chain reaction and BDNF protein by Western blotting and enzyme-linked immunosorbent assay in postmortem fusiform gyrus tissue from 11 patients with autism and 14 controls. BDNF mRNA levels were not different in the autism versus control samples, but total BDNF-like immunoreactive protein, measured by enzyme-linked immunosorbent assay, was greater in autism than in controls. Western blotting revealed greater pro-BDNF and less truncated BDNF in autism compared with controls. These data demonstrate that increased levels of BDNF-immunoreactive protein in autism are not transcriptionally driven. Increased pro-BDNF and reduced truncated BDNF are consistent with defective processing of pro-BDNF to its truncated form. Distortion of the balance among the 3 BDNF isoforms, each of which may exhibit different biological activities, could lead to changes in connectivity and synaptic plasticity and, hence, behavior. Thus, imbalance in proteolytic isoforms is a possible new mechanism for altered synaptic plasticity leading to autism.

Downregulation of brain-derived neurotrophic factor (BDNF) in the cortex occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival, synaptic plasticity, and memory, BDNF reduction may contribute to synaptic and cellular loss and memory deficits characteristic of AD.In vitroevidence suggests that amyloid-β (Aβ) contributes to BDNF downregulation in AD, but the specific Aβ aggregation state responsible for this downregulationin vivois unknown. In the present study, we examined cortical levels of BDNF mRNA in three different transgenic AD mouse models harboring mutations inAPPresulting in Aβ overproduction, and in a genetic mouse model of Down syndrome. Two of the three Aβ transgenic strains (APPNLhand TgCRND8) exhibited significantly decreased cortical BDNF mRNA levels compared with wild-type mice, whereas neither the other strain (APPswe/PS-1) nor the Down syndrome mouse model (Ts65Dn) was affected. OnlyAPPNLhand TgCRND8 mice expressed high Aβ42/Aβ40ratios and larger SDS-stable Aβ oligomers (∼115 kDa). TgCRND8 mice exhibited downregulation of BDNF transcripts III and IV; transcript IV is also downregulated in AD. Furthermore, in all transgenic mouse strains, there was a correlation between levels of large oligomers, Aβ42/Aβ40, and severity of BDNF decrease. These data show that the amount and species of Aβ vary among transgenic mouse models of AD and are negatively correlated with BDNF levels. These findings also suggest that the effect of Aβ on decreased BDNF expression is specific to the aggregation state of Aβ and is dependent on large oligomers.

Alzheimer's disease (AD) is a senile dementia characterized by amyloid plaques, neurofibrillary tangles, and synaptic and cell loss. The “amyloid cascade” hypothesis suggests that amyloid-β (Aβ), the peptide deposited as amyloid plaques, is the primary insult in AD. However, debate continues over the mechanism of Aβ toxicity and whether fibrillar or oligomeric Aβ is the active species of the peptide that ultimately causes the synaptic loss and dementia associated with AD. Brain-derived neurotrophic factor (BDNF) is required for survival and function of cells compromised in AD. Decreased BDNF causes defects in long-term potentiation and memory and correlates with cognitive decline. We previously demonstrated that BDNF reduction occurs early in the course of AD, suggesting that decreased BDNF may promote neuronal dysfunction in AD. We also demonstrated that three of seven human BDNF transcripts are specifically downregulated in AD. What pathological feature(s) of AD leads to the decreased BDNF is unknown.In this study, we administered both fibrillar and oligomeric conformations of Aβ1–42to differentiated SH-SY5Y, a human neuroblastoma cell line, and measured both phosphorylated cAMP response element-binding protein (CREB), a regulator of BDNF transcription, and BDNF total mRNA. We found that oligomeric but not fibrillar preparations of Aβ1–42significantly decrease both phosphorylated CREB and total BDNF mRNA. Furthermore, oligomeric Aβ1–42decreases BDNF transcripts IV and V in these cells, demonstrating that Aβ1–42downregulates the major BDNF transcript decreasedin vivoin the AD brain. Thus, oligomeric Aβ1–42could compromise neuronal function, causing memory loss and cognitive dysfunction by downregulation of BDNF in AD.

In Alzheimer's disease, BDNF mRNA and protein levels are reduced to as low as 40% of normal. Mounting evidence suggests reduced BDNF is responsible for neuronal atrophy and cognitive dysfunction. To determine whether current mouse models of Alzheimer's disease have reduced BDNF levels. BDNF mRNA levels were measured by quantitative real–time RT–PCR in cortical tissues from various mouse models of Alzheimer's disease, including APP, PS–1, APP/PS–1, CRND8, and Ts65Dn, and their wild type littermate controls. Ts65Dn mice carry three copies of mouse chromosome 16 and therefore over–express mouse APP. CRND8 mice over–express human APP carrying the Swedish and Indiana mutations. The APP, PS–1 and APP–PS–1 mice have a targeted replacement of mouse APP with APP containing the Swedish mutations and humanized A–beta, under control of the endogenous promoter, and thus do not over–express APP. BDNF mRNA levels were decreased in all mouse models containing mutations in the APP gene. BDNF mRNA levels were reduced by 41% in 11–12 month old CRND8 mice compared to controls. BDNF mRNA levels were also significantly reduced in 15–18 month old APP and APP/PS–1 mice, but not in mice carrying only the PS–1 mutation. BDNF levels were unchanged in 18–21 month old Ts65Dn mice compared to controls, indicating that over–expression of murine APP without mutation is insufficient to down–regulate BDNF, and that defective retrograde transport in these mice, which is known to result in accumulation of NGF in cholinergic target tissues, does not influence cortical BDNF mRNA levels. In summary, mutation(s) in APP alone are sufficient to down–regulate BDNF mRNA in cortical tissue of transgenic mice.