•Aging decreases spatial searching in wild-type mice.•Reelin cKO exacerbates and accelerates age-related spatial impairments.•Reelin cKO with P301S-MAPT (PS19) further accelerates and exacerbates ...spatial impairments.•Aged Reelin cKO mice have altered context learning in Trace Fear Conditioning.
The hippocampal formation (HF) is a neuroanatomical region essential for learning and memory. As one of the earliest regions to display the histopathological hallmarks of Alzheimer’s disease (AD), determining the specific mechanisms of the HF’s vulnerability is of capital importance. Reelin, a glycoprotein crucial in cortical lamination during embryonic neurogenesis, has an uncommon expression pattern within the HF and has been implicated in both learning and AD pathogenesis. We hypothesized that Reelin deficiency would expedite behavioral impairments which accompany normal aging. Additionally, we hypothesized that Reelin deficiency in the presence of mutated human microtubule associated protein tau (MAPT) would further impair hippocampal function. To test our hypothesis, we utilized cohorts of aged mice, aged mice with Reelin conditional knockout (RcKO), and adult mice with both RcKO and MAPT in the Barnes maze and Trace fear conditioning. Consistent with prior literature, increased age in wild-type mice was sufficient to reduce spatial searching in the Barnes maze. Increased age both exacerbated spatial impairments and altered context learning in RcKO mice. Lastly, adult mice with both RcKO and the MAPT transgene displayed both the lowest age-of-onset and most severe spatial learning deficits. In conclusion, Reelin deficiency when combined with AD risk-factors produced consistent impairments in spatial memory tasks. Furthermore, our results further implicate Reelin’s importance in both HF homeostasis and AD pathogenesis.
Fibroblast activation protein (FAP) is frequently expressed in the tumor stroma, whereas expression by normal organs is highly restricted. Despite these promising features, FAP-targeted therapies ...have shown limited success so far. FAP imaging offers new opportunities to select patients for FAP-targeted therapies and monitor tumor response. See related article by Lee et al., p. 5330.
Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Aβ oligomers cause synaptic dysfunction early in ...AD by enhancing long-term depression (LTD; a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal-enriched tyrosine phosphatase (STEP
). Reelin is a neuromodulator that signals through ApoE (apolipoprotein E) receptors to protect the synapse against Aβ toxicity (Durakoglugil et al., 2009) Reelin signaling is impaired by ApoE4, the most important genetic risk factor for AD, and Aβ-oligomers activate metabotropic glutamate receptors (Renner et al., 2010). We therefore asked whether Reelin might also affect mGluR-LTD. To this end, we induced chemical mGluR-LTD using DHPG (Dihydroxyphenylglycine), a selective mGluR5 agonist. We found that exogenous Reelin reduces the DHPG-induced increase in STEP
, prevents the dephosphorylation of GluA2, and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca
-permeable GluA2-lacking AMPA receptors along with higher STEP
levels, resulting in occlusion of DHPG-induced LTD in hippocampal CA1 neurons. We propose a model in which Reelin modulates local protein synthesis as well as AMPA receptor subunit composition through modulation of mGluR-mediated signaling with implications for memory consolidation or neurodegeneration.
Reelin is an important neuromodulator, which in the adult brain controls synaptic plasticity and protects against neurodegeneration. Amyloid-β has been shown to use mGluRs to induce synaptic depression through endocytosis of NMDA and AMPA receptors, a mechanism referred to as LTD, a paradigm of forgetfulness. Our results show that Reelin regulates the phosphatase STEP, which plays an important role in neurodegeneration, as well as the expression of calcium-permeable AMPA receptors, which play a role in memory formation. These data suggest that Reelin uses mGluR LTD pathways to regulate memory formation as well as neurodegeneration.
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