Modulation of Alzheimer-Like Synaptic and Cholinergic Deficits in Transgenic Mice by Human Apolipoprotein E Depends on Isoform , Aging, and Overexpression of Amyloid β Peptides But Not on Plaque Formation

Dec 18, 2002The Journal of neuroscience : the official journal of the Society for Neuroscience

How human apolipoprotein E types, aging, and excess amyloid beta affect Alzheimer-like nerve cell and chemical problems in mice without depending on plaque buildup

AI simplified

Alzheimers & Treatments on OpenScience ↗PubMed ↗DOI ↗

Abstract

ApoE3 delays synaptic deficits associated with aging and amyloid beta, while apoE4 does not.

ApoE isoforms E3 and E4 differentially influence Alzheimer's disease risk and age of onset.
ApoE4 promotes the accumulation of amyloid beta peptides in the brain compared to apoE3.
Cognitive decline correlates more strongly with synaptic and cholinergic deficits than with plaque load.
Old mice expressing apoE4 exhibited synaptic deficits before the formation of amyloid plaques.
Despite higher plaque levels, old hAPP/apoE4 and hAPP/apoE3 mice showed similar synaptic deficits.
ApoE3 may provide protection against age-related synaptic decline through mechanisms independent of plaque formation.

AI simplified

The most frequent human apolipoprotein (apo) E isoforms, E3 and E4, differentially affect Alzheimer's disease (AD) risk (E4 > E3) and age of onset (E4 < E3). Compared with apoE3, apoE4 promotes the cerebral deposition of amyloid beta (Abeta) peptides, which are derived from the amyloid precursor protein (APP) and play a central role in AD. However, it is uncertain whether Abeta deposition into plaques is the main mechanism by which apoE isoforms affect AD. We analyzed murine apoE-deficient transgenic mice expressing in their brains human APP (hAPP) and Abeta together with apoE3 or apoE4. Because cognitive decline in AD correlates better with decreases in synaptophysin-immunoreactive presynaptic terminals, choline acetyltransferase (ChAT) activity, and ChAT-positive fibers than with plaque load, we compared these parameters in hAPP/apoE3 and hAPP/apoE4 mice and singly transgenic controls at 6-7, 12-15, and 19-24 months of age. Brain aging in the context of high levels of nondeposited human Abeta resulted in progressive synaptic/cholinergic deficits. ApoE3 delayed the synaptic deficits until old age, whereas apoE4 was not protective at any of the ages analyzed. Old hAPP/apoE4 mice had more plaques than old hAPP/apoE3 mice, but synaptic/cholinergic deficits preceded plaque formation in hAPP/apoE4 mice. Moreover, despite their different plaque loads, old hAPP/apoE4 and hAPP/apoE3 mice had comparable synaptic/cholinergic deficits, and these deficits were found not only in the hippocampus but also in the neocortex, which in most mice contained no plaques. Thus, apoE3, but not apoE4, delays age- and Abeta-dependent synaptic deficits through a plaque-independent mechanism. This difference could contribute to the differential effects of apoE isoforms on the risk and onset of AD.

Full Text

Full text is available at the source.

View full text ↗

Modulation of Alzheimer-Like Synaptic and Cholinergic Deficits in Transgenic Mice by Human Apolipoprotein E Depends on Isoform , Aging, and Overexpression of Amyloid β Peptides But Not on Plaque Formation

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the alzheimers & treatments brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the alzheimers & treatments brief