Alzheimer’s disease (AD) is characterized by a progressive phenotypic downregulation of markers within cholinergic basal forebrain (CBF) neurons, frank CBF cell loss and reduced cortical choline ac...

Dysfunction of nerve growth factor (NGF) and its high (TrkA) and low (p75^NTR) affinity receptors has been suggested to underlie the selective degeneration of the nucleus basalis (NB) cholinergic cortical projection neurons in end stage Alzheimer disease (AD). Whether the NGF system is dysfunctional during the prodromal stages of AD has only recently been evaluated. Surprisingly, the number of choline acetyltransferase-containing neurons remains stable despite a significant reduction in NGF receptor-positive cells in people with mild cognitive impairment (MCI), suggesting a phenotypic NGF receptor downregulation but not a frank loss of NB neurons during prodromal AD. Moreover, there is a loss of cortical TrkA in the face of stable p75^NTR and increased proNGF levels, the precursor molecule of mature NGF, in early AD. Depending upon the cellular context these changes may result in increased pro-apoptotic signaling, cell survival, or a defect in retrograde transport mechanisms. Alterations in NGF and its receptors within the cholinotrophic NB system in early AD suggest that NGF-mediated cell signaling is required for the long-term survival of these neurons. Therapeutic neurotrophic intervention might delay or prevent NB neuron degeneration and preserve cholinergic cortical function during prodromal AD.

Purpose. To determine whether β-amyloid (Aβ) deposition affects the structure and function of the retina of the APPswe/PS1ΔE9 transgenic (tg) mouse model of Alzheimer’s disease. methods. Retinas from 12- to 19-month old APPswe/PS1ΔE9 tg and age-matched non-transgenic (ntg) littermates were single or double stained with thioflavine-S and antibodies against Aβ, glial fibrilar acidic protein (GFAP), microglial marker F4/80, choline acetyltransferase (ChAT), and syntaxin 1. Quantification of thioflavine-S positive plaques and retinal layer thickness was analyzed semi-quantitatively, whereas microglial cell size and levels of F4/80 immunoreactivity were evaluated using a densitometry program. Scotopic electroretinogram (ERG) recording was used to investigate retinal physiology in these mice. results. Thioflavine-S positive plaques appeared at 12 months in the retinas of APPswe/PS1ΔE9 tg mice with the majority of plaques in the outer and inner plexiform layers. Plaques were embedded in the inner plexiform layer strata displaying syntaxin 1 and ChAT. The number and size of the plaques in the retina increased with age. Plaques appeared earlier and in greater numbers in females than in male tg littermate mice. Microglial activity was significantly increased in the retinas of APPswe/PS1ΔE9 tg mice. Although we did not detect neuronal degeneration in the retina, ERG recordings revealed a significant reduction in the amplitudes of a- and b-waves in aged APPswe/PS1ΔE9 tg compared to ntg littermates. conclusions. The present findings suggest that Aβ deposition disrupts retinal structure and may contribute to the visual deficits seen in aged APPswe/PS1ΔE9 tg mice. Whether Aβ is involved in other forms of age-related retinal dysfunction is unclear.