Gillian C. Gregory

Pick Bodies in a Family with Presenilin-1 Alzheimer's Disease

Presenilin‐1 (PS‐1) mutations can cause Picks disease without evidence of Alzheimers disease (AD). We describe a family with a PS‐1 M146L mutation and both Pick bodies and AD. Sarkosyl‐insoluble hyperphosphorylated tau showed three bands consistent with AD, although dephosphorylation showed primarily three‐repeat isoforms. M146L mutant PS‐1 may predispose to both Picks disease and AD by affecting multiple intracellular pathways involving tau phosphorylation and amyloid metabolism. Ann Neurol 2005;57:139–143

What is the dominant aβ species in human brain tissue? A review

Epub ahead of print: December 2004 Interest in the beta amyloid (Aβ) peptides continues to grow due to their known accumulation in the brains of patients with Alzheimer’s disease and recent tantalising evidence that reducing such accumulations can reverse disease-associated functional deficits. Aβ peptides are naturally produced in every cell by proteolytic cleavage of the amyloid precursor protein with two main alloforms (40 or 42 amino acids) both of which are disease associated. The identification that genetic mutations causing Alzheimer’s disease impact on Aβ production and clearance have allowed for the manipulation of these pathways in cellular and animal models. These studies show that the amount and type of Aβ in the brain has significant consequences on neural function. However, there have been significant difficulties in the conversion of these findings into successful treatments in humans. In this review we concentrate on data from human studies to determine any comparative differences in Aβ production and clearance that may assist with better treatment design and delivery. Aβ40 is the dominant peptide species in human cerebrospinal fluid accounting for approximately 90% of total Aβ under normal conditions. However, similar studies using disease free human brain tissue do not correlate with these findings. In these studies, concentrations of Aβ40 are low with Aβ42 often identified as the dominant species. The data suggest preferential brain tissue utilisation and/or clearance of Aβ40 compared with Aβ42, findings which may have been predicted by their physiochemical differences. In Alzheimer’s disease this equilibrium is disrupted significantly increasing Aβ peptide levels in brain tissue. The disease-specific increase in Aβ40 brain tissue levels in Alzheimer’s disease appears to be an important though overlooked pathological change compared with the welldocumented Aβ42 change observed both in the aged and in Alzheimer’s disease. These findings are discussed in association with Aβ peptide function and a model of toxicity developed.

Positional effects of presenilin-1 mutations on tau phosphorylation in cortical plaques

Mutations in presenilin-1 (PS-1) account for the majority of familial Alzheimers disease (AD). While increasing Abeta42 is one mechanism whereby PS-1 mutations are thought to exert their pathogenic effect, little is known about the role of tau in PS-1 AD. This study compares staining (AT8 and tau-2), morphology and quantity of tau-immunoreactive cortical plaques in six PS-1 and five sporadic AD cases. The densities of tau-positive plaques differentiated PS-1 from sporadic AD cases. All PS-1 cases demonstrated a greater than 6-fold increase in tau-2-positive plaques. In PS-1 cases with mutations in exons 5 and 6, there was an increase in classical AD plaques containing hyperphosphorylated tau (AT8- and tau 2-positive). However, cases with exon 8 and 9 mutations had numerous cotton wool plaques containing nonhyperphosphorylated tau (tau-2-positive, AT8-negative). These findings suggest that PS-1 mutations increase tau deposition while mutation-specific cellular responses determine phosphorylation events and may influence cell death mechanisms.

Differences in regional brain atrophy in genetic forms of Alzheimer's disease.

Multiple degenerative hallmarks characterize Alzheimers disease: insoluble protein deposition, neuronal loss and cortical atrophy. Atrophy begins in the medial temporal lobe and becomes global by end stage. In a small proportion of cases, these tissue changes are caused by mutations in three known genes. These cases are affected earlier in life and have more abundant protein deposition, which may indicate greater tissue atrophy and degeneration. This issue remains unresolved. Grey matter atrophy in different cortical regions was determined in genetic cases of Alzheimers disease (N = 13) and compared to sporadic cases (N = 13) and non-diseased controls (N = 23). Genetic mutations were found to influence the degree and regional pattern of atrophy. The majority of cases had greater medial temporal atrophy than sporadic disease, suggesting that abnormalities affecting Abeta metabolism selectively increase hippocampal degeneration. Cases with mutations in presenilin-1 demonstrated additional increased frontotemporal atrophy. This effect may be due to the influence of presenilin-1 on tau phosphorylation and metabolism. These differences may explain the earlier onset ages in these different forms of Alzheimers disease.

Phosphorylation of soluble tau differs in Pick’s disease and Alzheimer’s disease brains

Frontotemporal lobar degeneration (FTLD) is a common cause of presenile dementia characterised by behavioural and language disturbances. Pick’s disease (PiD) is a subtype of FTLD, which presents with intraneuronal inclusions consisting of hyperphosphorylated tau protein aggregates. Although Alzheimer’s disease (AD) is also characterised by tau lesions, these are both histologically and biochemically distinct from the tau aggregates found in PiD. What determines the distinct characteristics of these tau lesions is unknown. As phosphorylated, soluble tau has been suggested to be the precursor of tau aggregates, we compared both the level and phosphorylation profile of tau in tissue extracts of AD and PiD brains to determine whether the differences in the tau lesions are reflected by differences in soluble tau. Levels of soluble tau were decreased in AD but not PiD. In addition, soluble tau was phosphorylated to a greater extent in AD than in PiD and displayed a different phosphorylation profile in the two disorders. Consistently, tau kinases were activated to different degrees in AD compared with PiD. Such differences in solubility and phosphorylation may contribute, at least in part, to the formation of distinct tau deposits, but may also have implications for the clinical differences between AD and PiD.

Novel ‘inflammatory plaque’ pathology in presenilin‐1 Alzheimer's disease

Inflammation, in the form of reactive astrocytes and microglia, is thought to play an important role in Alzheimers disease (AD) pathogenesis where it correlates with brain atrophy and disease severity. The Aβ protein, which comprises senile plaques, is thought to be responsible for initiating this inflammatory response. Despite having a more aggressive disease process and greater Aβ deposition, few studies have investigated inflammation in early onset AD cases with mutations in the presenilin‐1 (PS‐1) gene. In fact, many researchers place importance on a variant plaque pathology in PS‐1 cases, known as cotton wool plaques, which lack significant inflammatory infiltrate. We investigated the association between inflammation and plaque pathology in PS‐1 AD. Classic cored, cotton wool and diffuse Aβ plaques were observed in all cases. PS‐1 cases also exhibited a novel plaque pathology with a significantly greater inflammatory response in the form of reactive microglia and astrocytes. These ‘inflammatory plaques’ consisted of a dense cresyl violet‐, silver‐, and thioflavin S‐positive, but Aβ‐, tau‐, apolipoprotein E (ApoE)‐, non‐Aβ component of Alzheimers disease amyloid (NAC)‐ and PS‐1‐negative core. These findings indicate potent stimulator(s) of inflammation that are not typical of the Aβ that accumulates in the pathological hallmarks of sporadic AD. Identification of this substance may be important for the development of future therapeutic strategies.

No association of spastic paraparesis genes in PSEN1 Alzheimer's disease with spastic paraparesis.

Familial Alzheimers disease due to presenilin 1 (PSEN1) mutations shows considerable phenotypic variability with differences in neuropathology and neurological symptoms. Spastic paraparesis is a common neurological phenotype associated with Alzheimers disease arising from PSEN1 mutations. To investigate whether known genes that cause spastic paraparesis could act as Alzheimers disease-modifier genes, we sequenced nine spastic paraparesis genes in three Alzheimers disease families with PSEN1 exon 9 deletions. We did not observe any correlation of polymorphisms or mutations in the nine spastic paraparesis genes with the variable phenotype seen in families with Alzheimers disease and spastic paraparesis. These results suggest a need for a continuing search for genes that cause the phenotypic variation in Alzheimers disease and spastic paraparesis.

Physiologic and Neurotoxic Properties of Aβ Peptides

Alzheimer’s disease (AD) is characterized by a gradual decline of numerous cognitive processes, culminating in dementia and neurodegeneration. It is the most common form of dementia and a significant cause of death in the elderly. Definitive diagnosis of AD requires the presence of the extracellular accumulation of Aβ peptides in senile plaques in the cortex of the brain (Fig. 11.1) [1]. β-Amyloid (Aβ) peptides are ∼4-kDa polypeptides with the main alloforms consisting of 40 and 42 amino acids. Analysis of the insoluble protein fraction has identified the longer Aβ42 alloform as the predominant peptide species in the neuropathologic accumulations (see [2]), although Aβ peptides of variable length accumulate within plaques [3]–[8]. The association between the abnormal accumulation of Aβ peptides in the brain and dementia is strong evidence that Aβ peptides are vital for normal brain functioning.