Abstract
A decrease in brain-derived neurotrophic factor (BDNF), a neurotrophin essential for synaptic function, plasticity and neuronal survival, is evident early in the progression of Alzheimer’s disease (AD), being apparent in subjects with mild cognitive impairment or mild AD, and both proBDNF and mature BDNF levels are positively correlated with cognitive measures. BDNF delivery is, therefore, considered of great interest as a potentially useful therapeutic strategy to contrast AD. Invasive BDNF administration has indeed been recently used in animal models of AD with promising results in rescuing memory deficits, synaptic density and cell loss. Here, we tested whether non-invasive intranasal administration of different BDNF concentrations after the onset of cognitive and anatomical deficits (6 months of age) could rescue neuropathological and memory deficits in AD11 mice, a model of NGF deprivation-induced neurodegeneration. In addition to AD hallmarks, we investigated BDNF effects on microglia presence in the brain of AD11 mice, since alterations in microglia activation have been associated with ageing-related cognitive decline and with the progression of neurodegenerative diseases, including AD. We found that intranasal delivery of 42 pmol BDNF (1 μM), but not PBS, was sufficient to completely rescue performance of AD11 mice both in the object recognition test and in the object context test. No further improvement was obtained with 420 pmol (10 μM) BDNF dose. The strong improvement in memory performance in BDNF-treated mice was not accompanied by an amelioration of AD-like pathology, Aβ burden, tau hyperphosphorylation and cholinergic deficit, but there was a dramatic decrease of CD11b immunoreactive brain microglia. These results reinforce the potential therapeutic uses of BDNF in AD and the non-invasive intranasal route as an effective delivery strategy of BDNF to the brain. They also strengthen the connection between neuroinflammation and neurodegenerative dementia and suggest microglia as a possible mediator of BDNF therapeutic actions in the brain.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system which is by far the most common cause of dementia in the world and still lacks effective therapeutic strategies [1]
At 6 months of age, AD11 mice already show a strong deficit in visual recognition memory and cholinergic deficits [22], amyloid-β (Aβ) clusters appear in proximity of dystrophic neurites in the hippocampus and hyperphosphorylated tau are already detectable [23]
We found that brain-derived neurotrophic factor (BDNF) mRNA is still down-regulated in AD11 hippocampus (0.62 linear scale fold change), further reinforcing the rationale for a BDNF treatment
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system which is by far the most common cause of dementia in the world and still lacks effective therapeutic strategies [1]. BDNF is a polar protein that does not readily cross the blood–brain barrier To overcome this limit, preclinical studies with BDNF in aged rodents and mouse models over-expressing APP have been performed using invasive gene therapy approaches. Promising, the gene therapy approach has two main limits: (1) the invasiveness of the method to deliver the vector into the brain (2) the limited brain area reachable with injections, while more than one region could be positively affected by an increase in BDNF expression It remains unclear whether administering BDNF after the onset of cognitive decline would be an efficacious treatment. At this age, BDNF mRNA levels are decreased and that intranasal administration of BDNF could rescue memory deficits and decrease microglial activation
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