Endosomal-lysosomal mechanisms in amyloido-genesis and neurodegeneration: Animal models

Synposium:

s12

ENDOSOMAL-LYSOSOMAL GENESIS

MECHANISMS

AND NEURODEGENERATION:

IN

ANIMAL

AMYLOIDOMODELS

Ralph A Nixon, NYU School of Medicine/Nuthm Kline Institute, Orangeburg, NY; Anne M Catuldo. McLean Hospital/Harvard Medical School/Nathan Kline Inst., Belmont, MA; Paul M Mathews, Karen Duff; NYU School ofMedicine/Nuthun Kline Institute, Orangeburg, NY; Carolyn B Gum-u, Nathun Kline Institute. Orungeburg, NY; Panaiyr Mohan, NYU School of Mrdicin&Vuthan Kline Institute, Orangebur~, NY; Yirtg Jinng, Corrinne Pcterhofi Nathan Kline Institute. Orungrburg, NY Progressive activation of the lyaosomal system is a distinctive and early reaponse of neurons vulnerable to degenerate in AD and is an event that can initiate cell death~in certain apoptosis paradigms. Lysosomal system activation is also observed in tranagenic mice expressing human APPswe and is accentuated when a second transgene, PSI M146L, is introduced (PSIAPP mouse). Despite extensive P-amyloid deposition, however, lysosomal system abnormalities in PS/APP mice do not progress to the extent seen in AD and neurodegeneration is minimal. By contrast, chronic intmventricular delivery of the cyst&e-protease inhibitor, leupeptin, used to model aging-related lysoromal system alterations, induces extensive lyrosomal system changes in PSlAPP mice, which are comparable to those observed in late stage AD. These changes are associated with considerable neuronal atrophylchromatolysis that is not ~een in leupeptin-treated age-matched non-transgenic mice. Endocytosis, a major pathway to the lysosome, is also upregulated very early in sporadic AD (SAD) and Down Syndrome (DS). Early endosomes, the first vacuolar compartment of the endocytic pathway and a major site of Ab formation and Apo E internalization, begin to enlllrge markedly in pyramidal neurons prior to P-amyloid deposition in SAD and even before birth in DS. Endosomal enlargement ia accompanied by the appearance of AP immunoreactivity in some large early endosomes. Lysosomal system activation m AD brain results in the increased trafficking of lysosomal hydrolases to early endosomes and, when the latter abnormality is modeled in transfected cells, AP secretion increases markedly (Mathews, this mtg). These findings wgge\t an endosomal mechanism for increased amyloidogenesia relevant to SAD and DS. Ts65Dn mice, a model of human DS, qhow endosomal enlargement and AP colocalization similar to that seen in AD, suggesting that these mice may be a valuable model of early stage AD (Cataldo, this mtg). Our rewlt, support the hypotheais that the prominent endosomal-lysosomal abnormalities seen in AD brain may be critical to diuea,e pathogenesis and suggest suitable animal models 1” which to further explore these relationships. (Supported by the NIA).

Symposium: Assessment of Evolving ties in Alzheimer’s Disease

13221 S/even

School

NEUROPSYCHOLOGICAL MER’S

CORRELATES

Brain Abnormali-

OF EARLY

ALZHEI-

DISEASE

H. Ferris, Alan Kluger, James Gulornb, Barr:y R&berg, of Medicine, New York, NY

New York Utliversity

Neuropaychological measures can be aensitlve behavioral correlates of the earliest brain pathology associated with Alzheimer’s disease (AD). As soon as early AD pathology impairs the function of brain systems in the hlppocampua and related structures that iire critical for effective information proceasing required for memory and related cognitive functions, appropriately designed psychometric test paradigm? potentially can identify individuala at high risk for developing clinical AD. Since an important research goal is to develop treatments that inay slow or halt the progression of early AD pathology, such sensitive cognitive measures will play an important role in the design of clinical trials for the prevention of AD. For example. psychometric method> may he used to select “enriched” sample\ of subject\ who are at mcreased risk for showing measurable cognitive decline over relatively brief observation perlads of l-3 years. Such measures would also be useful in the validation of early biological markers of AD. In current studies of individuals with mild cognitive impairment (MCI), sensitive memory tests (e.g., the NYU Paragraph Recall Test) are already available that can identify cases who are at high risk of receivmg a diagnosis of AD within several years. In future studies of “normal” elderly subjects, where the goal is to slow cognitive decline and to delay conversion to MCI or AD, enrichment strategies will also be needed to reduce both sample aiLe and Ftudy duration while maintaining adequate statistical power. Difficulties in differentiating age related cogmtwe decline (ARCD) from the earliest AD related changes include the qualitative similarity between age related and very early AD related deficits, and the lack of information on an individual’5 premorbid level of performance. Nevertheless, sensitive test paradigms developed by several groups, including procedures derived from basic animal research on hippocampal information processing, have great potential for providing cognitive correlates of very early AD pathology. Thus, current research to Identify neuropsychological markers of AD risk may provide sensitive behavioral correlate\ of the earliest brain changes associated with AD pathology.

A.ssr.wmmt

13231NEURAL

of Evolving CIRCUITS

Bruin Abnormalities

COMPROMISED

in Alzheimer’s

IN THE

AGED

Disease

BRAIN

John Henm Morrison. Mount Sinai School qf Medicine. New York. NY Neocortical and hippocampal circuits display a high degree of neurochemical specificity and heterogeneity, with certain attributes perhaps leaving a circuit vulnerable to aging and other attributes conferring an element of protection. While neurodegenerative disorders such as Abheimer’s Disease (AD) are characterized by extensive yet selective neuron death that leads to dramatic functional decline, the neurobiological correlates of functional decline in normal aging are more likely to be subtle neurochemical and morphologic alterations of key circuits in the absence of frank neuronal degeneration. More specifically, in AD, the perforant path interconnecting entorhinal cortex and hippocampus is devastated, as are certain corticocortical interconnections between association areas, and the dementia of AD represents the resultant inability of these key cortical and hippocampal area5 to function m a cohesive, distributed fashion once these circuits degenerate. Recent studies suggest that, in contrast, neuron death is very restricted in normal aging, and unlikely to account for age-related impairment in neocortical and hippocampal function\. However, certain circuits are vulnerable to age-related shifts in neurochemical phenotype that might impair function. The qualitative and quantitative difference7 between aging and Alzheimer’s disease with respect to specific neocortical and hippocampal circuits will be discussed, and age-related changes in biochemical attributes and synaptic integrity of hippocampal circuits will he explored that might mediate functional decline in the absence of neuron death. The glutamate receptors (e.g., NMDA receptors) appear to be particularly relevant as a substrate for age-related memory decline and will be discussed in the context of their correlation with performance and age- and endocrine-related modifications that might impair performance.

STEREOLOGICAL

APPROACHES

TO

ALZHEIMER’S

DISEASE

ANDAGERELATEDNEURONALLOSS

Mark J West. Universiry ofAarhu.s, Awhus Denmark: Claudia Kawas, Johns Hopkins Unilvrsity School of Medicine. Bultitnore. MD; Lee J Mar-tin, Jum C Troncoso. Johm Hopkim IJniversity, Baltimore, MD The total number of neurons in each of the major subreglow of the hippocampal formation have been estimated in groups of subjects with clinical and pathological diagnoses of Alzheimer’s disease (AD) and age matched controls (AMC). The estimates were obtained with modem, unbiased, stereologxal techniques. Comparisons of group means indicate the presence of significant AD related neuronal loss in the dentate hilus (29%), CAI (54%), and subiculum (31%), but not in the dentate gyros or CA3-2. The regional pattern and the extent of the neuronal loss are ecsentially the same as those reported earlier by West, et al., (The Lancet 344~76’). 772, 1994). All material used in the study was obtained from the Alzheimer’s Disease Research Center at Johns Hopkins University and all individuala in the AD group had a clinical diagnosis based on NINCDS-ADRDA criteria and a pathological diagnosis based on CERAD criteria. The results of this study confirm that the extent of neuron loss related to AD varies among hippocampal subdivisions and is most pronounced in CAl, where over half of the neurons are lost with AD. Stereological studies of thir type can prowde a unique basis for designing additional behavioral and molecular biological studies. On the basis of these findings, a series of molecular biological studies aimed at identifying the molecular events associated with AD related neuronal loss has been initiated in CA]. In addition, a preliminary examination of psychometric correlates of neuron loss in the various hippocampal subdivision\ of subjects diagnosed as having AD and controls, indicates that there is a highly significant correlation between the number of neurons in CA1 and the Mini Mental State Examinatmn (MMSE) score (r > 0.74, p < 0.02, n = 21). Tlus correlation may provide a fruitful basis for developing new criteria for the diagnosis of AD. Supported 17~:The ADRC at Johns Hopkins Univenity NIH Grant AG OS146

AMYLOID 13251THE ITIVE ABETA

PARADOX DEPOSITS

RESOLVED LEAD

TO

_ THIOFLAVINE LOCAL

NEUROPIL

S POSDAM-

AGEANDNEURONALDEATH

The amyloid paradox derives from the facts that, although genetic evidence overwhelmingly supports the idea that Abeta ia central to Alzheimer disease development and progression, measures of amyloid deposition do not correlate well with duration or severity of clinical Fymptoms, neuronal loss, or local alterations in the neuropil. these facts are remforced by the development of trangenic models which dvelop extraordinarily high amyloid burdens, but no global neuronal loss. We have used confocal microscopy and 3 dimensional reconstrucnons of plaques using a variety of stains to detemnne If a subpopulation of plaques might be responsible for neurop~l