Neuron Loss in Alzheimer's Disease: Translation in Transgenic Mouse Models

Abstract

Transgenic mouse models represent an essential tool for the exploration of Alzheimer's disease (AD) pathological mechanisms and the development of novel treatments, which at present provide only symptomatic and transient effects. While a variety of mouse models successfully reflects the main neuropathological hallmarks of AD, such as extracellular amyloid-β (Aβ) deposits, intracellular accumulation of Tau protein, the development of micro- and astrogliosis, as well as behavioral deficits, substantial neuron loss, as a key feature of the disease, seems to be more difficult to achieve. In this review, we summarize information on classic and more recent transgenic mouse models for AD, focusing in particular on loss of pyramidal, inter-, and cholinergic neurons. Although the cause of neuron loss in AD is still a matter of scientific debate, it seems to be linked to intraneuronal Aβ accumulation in several transgenic mouse models, especially in pyramidal neurons.

Keywords: Alzheimer’s disease; Amyloid precursor protein; amyloid β; intraneuronal Aβ; neuron loss; transgenic mice.

Figure 1

(A) Schematic representation of mutant and wildtype (WT) human amyloid precursor protein (APP), highlighting the positions of mutations frequently used in APP transgenic mouse models of AD (modified from [7]). Cleavage by β-secretase (BACE1) initiates the generation of Aβ peptides with the liberation of the soluble sAPPβ fragment. The membrane-bound APP C-terminal fragment (β-CTF) is further cleaved by the γ-secretase complex to liberate Aβ and the APP intracellular domain (AICD). (B) Amino acid sequences and numbering of the most common Aβ variants present in transgenic AD mouse models.

Figure 2

Intraneuronal Aβ accumulation in the CA1 region of 2- (A) and 6-month-old (B) APP/PS1KI mice, as well as in cortical layers ((C), 2-month-old). Six-month-old homozygous Tg4-42 mouse showing CA1 neuron loss together with intraneuronal Aβ accumulation (D,E) (higher magnification of area indicated in (D)).