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.