The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

Abstract

In view of the increase in the aging population and the unavoidable parallel increase in the incidence of age-related neurodegenerative diseases, a key challenge in neuroscience is the identification of clinical signatures which change with age and impact on neuronal and cognitive function. Early diagnosis offers the possibility of early therapeutic intervention, thus magnetic resonance imaging (MRI) is potentially a powerful diagnostic tool. We evaluated age-related changes in relaxometry, blood flow, and blood-brain barrier (BBB) permeability in the rat by magnetic resonance imaging and assessed these changes in the context of the age-related decrease in synaptic plasticity. We report that T2 relaxation time was decreased with age; this was coupled with a decrease in gray matter perfusion, suggesting that the observed microglial activation, as identified by increased expression of CD11b, MHCII, and CD68 by immunohistochemistry, flow cytometry, or polymerase chain reaction (PCR), might be a downstream consequence of these changes. Increased permeability of the blood-brain barrier was observed in the perivascular area and the hippocampus of aged, compared with young, rats. Similarly there was an age-related increase in CD45-positive cells by flow cytometry, which are most likely infiltrating macrophages, with a parallel increase in the messenger mRNA expression of chemokines IP-10 and MCP-1. These combined changes may contribute to the deficit in long-term potentiation (LTP) in perforant path-granule cell synapses of aged animals.

Respiratory infection promotes T cell infiltration and amyloid-β deposition in APP/PS1 mice

“…Interestingly, increased expression of these chemokines has been reported in AD (Tripathy et al, 2007(Tripathy et al, , 2010Xia et al, 2000), whereas increased T cell expression of CCR5 and CXCR2 has also been reported (Liu et al, 2010;Man et al, 2007;Reale et al, 2008). Infiltration of immune cells may also be a consequence of increased bloodebrain barrier permeability, which we have observed in aged animals (Blau et al, 2012) and APP/PS1 mice (Minogue et al, unpublished), and which is known to occur after B. pertussis infection (Linthicum et al, 1982).…”

Age-associated physiological and pathological changes at the blood–brain barrier: A review

“…Astrocyte proliferation: Increased number and size GFAP expression: Increased Rodriguez-Arellano et al, 34 Harris et al 37 Chisholm and Sohrabji, 38 Middeldorp 69 Blau et al 69 Lucke-Wold et al 75 Lucke-Wold et al, 75 Cerbai et al 76 Buschini et al 77 Alzheimer's disease such as vascular-mediated Ab-independent neurodegeneration, regulation of Ab clearance and contributions to tau pathology, neuronal loss and cognitive decline. 93 Pericytes demonstrate large numbers of intracellular inclusions, pinocytotic vesicles, large lipid granules and mitochondrial abnormalities suggesting cellular dysfunction and/or degeneration.…”

The mechanisms of action of flavonoids in the brain: Direct versus indirect effects

“…This close relationship between plasticity and cerebral blood flow is illustrated in studies showing that declines in brain perfusion (e.g. aging, artificially induced models) affect LTP (224)(225)(226). As such, the beneficial effects of flavonoids might be particularly relevant to alleviate or prevent declines in vascularization of the brain and as such preserve synaptic function and cognitive abilities in aging and neurological disease.…”