Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses

Abstract

Increasing evidence from mouse models of Alzheimer's disease shows that overexpression of a mutant form of the amyloid precursor protein (APP) and its product, ␤-amyloid peptide, initiate pathological changes before amyloid deposition. To evaluate the cytological basis for one of these early changes, namely reduced volume of the dentate gyrus (DG), we have used high-throughput diOlistic cell loading and 3D neuronal reconstruction to investigate potential dendritic pathology of granule cells (GCs) in 90-day-old PDAPP mice. Labeled GCs from fixed hippocampal slices were selected randomly and imaged digitally by using confocal laserscanning microscopy. The dendritic complexity of GCs was quantified according to subordinate morphological parameters, including soma position within the granule cell layer (superficial versus deep) and topographic location within the DG (dorsal versus ventral blade) along the anterior-posterior hippocampal axis. Initial analysis, which included all sampled GC types, revealed a 12% reduction of total dendritic length in PDAPP mice compared with littermate controls. Further analysis, performed with refined subgroups, found that superficially located GCs in the dorsal blade were profoundly altered, exhibiting a 23% loss in total dendritic length, whereas neurons in the ventral blade were unaffected. Superficial GCs were particularly vulnerable (a 32% reduction) in the posterior region of the DG. Furthermore, the dendritic reductions of this select group were uniformly localized within middleto-outer portions of the dentate molecular layer. We conclude that substantial dendritic pathology is evident in 90-day-old PDAPP mice for a spatially defined subset of GCs well before amyloid accumulation occurs.T he classical neuropathological hallmarks of Alzheimer's disease (AD) include the presence of neurofibrillary tangles within neurons and extracellular cerebrovascular, diffuse, and neuritic plaques (1). The key molecular constituent of the plaque is ␤-amyloid (A␤), a 39-to 43-amino acid amyloidogenic peptide, which is a product of the proteolytic processing of the amyloid precursor protein (APP) (2). It has been shown that familial APP mutations may facilitate AD-like neuropathological changes by accelerating aberrant APP proteolytic processing. This hypothesis has been reinforced by evidence from transgenic (Tg) mouse models of AD in which overexpression of mutant APP results in amyloid deposition (3-10). Neuritic dystrophy associated with the deposits of A␤ in AD brains is evidenced by progressive dendritic dystrophy within the hippocampal complex (11-17). Although the assumption has been that A␤ deposition leads to neuritic dystrophy that would impair hippocampal function (18,19), the causal links between the deposition and pathology have been largely inferential, with minimal data available on the time course of these events.Tg mouse models have provided a unique opportunity to characterize A␤-induced neuropathology, including the nature and time of onset of the physiological and morpholog...

Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

“…The perforant path that projects from the entorhinal cortex to the dentate gyrus is among the most vulnerable pathways in cortex with respect to both aging and AD pathology Gazzaley et al, 1997). In addition, there have been recent reports of decreased spine density and alterations in dendritic branching in the outer molecular layer of the dentate gyrus in both Tg2576 mice and PDAPP mice (Wu et al, 2004;Jacobsen et al, 2006). These findings and our quantitative electron microscope results support the hypothesis that the outer molecular layer of the dentate gyrus is especially vulnerable to the effects of APP overexpression.…”

Age-Related Loss of Synaptophysin Immunoreactive Presynaptic Boutons within the Hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L Transgenic Mice

“…2 and 66 -68 ). In this regard, a 12% reduction in total dendritic length of hippocampal granule cells was found in 3-month-old APP V717F transgenic mice, ie, before amyloid deposition, in a recent study by Wu et al 69 Certain subsets of granule cells (superficially located granule cells in the dorsal blade of the dentate gyrus) even exhibited a 23% loss of total dendritic length at 3 months of age. 69 The authors of this study hypothesized that these alterations were due to elevated levels of soluble forms of A␤, induced by the overexpression of APP.…”

“…In this regard, a 12% reduction in total dendritic length of hippocampal granule cells was found in 3-month-old APP V717F transgenic mice, ie, before amyloid deposition, in a recent study by Wu et al 69 Certain subsets of granule cells (superficially located granule cells in the dorsal blade of the dentate gyrus) even exhibited a 23% loss of total dendritic length at 3 months of age. 69 The authors of this study hypothesized that these alterations were due to elevated levels of soluble forms of A␤, induced by the overexpression of APP. 69 Comparably, one may speculate that at least part of the 30% (49% minus 19% age-related loss of SIPB numbers seen within SM of the wild-type control mice) transgene-induced age-related reduction in SIPB numbers in regions free of A␤ deposits within SM of APP751 SL /PS1 M146L mice is due to elevated levels of soluble A␤.…”

“…69 The authors of this study hypothesized that these alterations were due to elevated levels of soluble forms of A␤, induced by the overexpression of APP. 69 Comparably, one may speculate that at least part of the 30% (49% minus 19% age-related loss of SIPB numbers seen within SM of the wild-type control mice) transgene-induced age-related reduction in SIPB numbers in regions free of A␤ deposits within SM of APP751 SL /PS1 M146L mice is due to elevated levels of soluble A␤. 5) Intraneuronal A␤.…”

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

“…MAP2 can also bind other neuronal proteins, including calcium channels (Davare et al 1999), MAP2 RNA transacting proteins (MARTA) (Rehbein et al 2000), CRMP5 (Brot et al 2010), neural cell adhesion molecule L1 (L1CAM) (Poplawski et al 2012), and the KIND domain containing RasGEF, very-KIND ). Changes in MAP2 expression levels have been linked to numerous neurological and neurodegenerative diseases such as schizophrenia (Rosoklija et al 2005) and epilepsy (Jalava et al 2007;Yan et al 2012), Alzheimer's disease (Canas et al 2009;Capetillo-Zarate et al 2006;Dziewczapolski et al 2009;Moolman et al 2004;Takahashi et al 2013;Wu et al 2004), spinal cord injury (Abdanipour et al 2014;Gonzalez et al 2009), stress (Yan et al 2010), myotonic dystrophy (Velazquez-Bernardino et al 2012), and prion diseases (Zhang and Dong 2012).…”