The major histological features of Alzheimer’s disease (AD) are the presence of neurofibrillary tangles (NFTs), amyloid plaques and neuronal loss. AD brains are further characterised by cerebral atrophy and inflammation. Approximately 5% of AD patients have familial Alzheimer’s disease (FAD), a genetic predisposition in which mutations in several genes have been identified: amyloid precursor protein (APP); apolipoprotein (ApoE4); presenilin 1 (PS-1) and; presenilin 2 (PS-2). These genetic mutations have been used to create transgenic mouse models of AD that can reproduce several aspects of the disease. One critical aspect is the accumulation of amyloid plaques; protein deposits of aggregated amyloidogenic peptides, formed by the proteolysis of the membrane bound APP. The amyloid cascade hypothesis proposes that it is the accumulation of soluble and insoluble forms of Aβ that causes the onset of secondary alterations such as NFTs and neuronal death (Hardy and Selkoe, 2002).
The mechanism whereby Aβ is involved in the pathophysiology of AD is poorly understood. Insoluble fibril forms were initially postulated to be the major pathologic form and then subsequently it was discovered that soluble oligomers of extracellular Aβ are toxic at synapses. More recently intraneuronal Aβ has been observed in human AD brain (Zhang et al., 2002, Gouras et al., 2000;Takahashi et al., 2002; Cataldo et al., 2004; Takahashi et al., 2004) and AD mouse models (Takahashi et al., 2002;Oddo et al., 2003; Schmitz et al., 2004), and may be linked to brain amyloidosis of NFT degeneration. Studies on post-mortem human AD brain indicated that soluble pools of Aβ42 correlate best with degree of cognitive loss (Lue 1999, McClean 1999, Naslund 2000) and are the most deleterious species, whereas aggregated, insoluble deposits have reduced pathogenicity (Walsh, Selkoe 2007). Intracellular and extracellular Aβ pools may be linked (D’andrea 2001).
These findings have led to Aβ becoming the leading target for experimental therapies and for early diagnosis using magnetic resonance imaging (MRI). NFTs have received less attention partly because tau pathology may be less specific for AD than Aβ pathology (although more specific to atrophy?) and research in mouse models has shown that tau pathology follows Aβ pathology (Gouras, 2000; Oddo, 2004). For the evaluation of immerging therapies and diagnostic methods it is crucial to understand the mechanisms for beta-amyloid detection by MRI and what it may represent regarding the neurobiology. Minimising the multiple pathologies in transgenic mouse models to beta-amyloid deposition increases the identification of factors specifically correlating with the neurotoxicity of beta-amyloid. There have been several strains of AD transgenic mice which develop beta-amyloid plaques but without NFTs or neurodegeneration. This may be useful when focussing studies on the mechanisms for the MRI contrast changes associated with beta-amyloid plaque lesions alone and where it is useful to have a less diseased tissue background. Using high magnetic field strengths, high spatial resolution imaging and relatively long acquisition times, individual beta-amyloid plaques can be resolved on T2 and T2* weighted MR imaging without the use of exogenous contrast agents (Benveniste et al., 1999; Jack et al., 2004; Jack et al., 2005; Lee et al., 2004; Poduslo et al., 2002; Vanhoutte et al., 2005; Zhang et al., 2004; Poduslo et al., 2002; Jack et al., 2004; Jack et al., 2005) and the compartmentalisation of iron within plaques leading to increased paramagnetic susceptibility has been postulated as a possible cause (Benveniste et al., 1999; Jack et al., 2004; Jack et al., 2005; Lee et al., 2004; Vanhoutte et al., 2005; Falangola et al., 2005b).